positron emission tomography and colorectal cancer
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Critical Reviews in Oncology/Hematology 77 (2011) 30–47
Positron emission tomography and colorectal cancer
Michael Lin a,b,c,∗, Karen Wong b,c,d, Weng Leong Ng b,c,e,Ivan Ho Shon a,b, Matthew Morgan c,f
a Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, Australiab University of New South Wales, Sydney, Australia
c South Western Sydney Colorectal Tumour Group, Sydney South West Area Health Service, Sydney, Australiad Department of Radiation Oncology, Liverpool Hospital, Sydney, Australiae Department of Medical Oncology, Liverpool Hospital, Sydney, Australia
f Department of Colorectal Surgery, Bankstown Hospital, Sydney, Australia
Accepted 30 April 2010
ontents
. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
. Positron emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312.1. PET and PET-CT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312.2. PET-CT colonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
. Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313.1. Initial staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.1.1. Rectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313.1.2. Colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.2. Staging of recurrent colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323.2.1. Evaluation of hepatic metastases for liver resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333.2.2. Assessment of local recurrence for salvage treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343.2.3. Early detection of biochemical recurrence (rising serum CEA levels) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343.2.4. To identify peritoneal carcinomatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.3. Prognostication and evaluation of treatment response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343.3.1. Neoadjuvant therapy for rectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353.3.2. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363.3.3. Local ablative therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.4. Radiotherapy planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383.5. Post-treatment surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403.6. Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403.7. Incidental colonic FDG uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
. Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.1. PET-MR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424.2. Non-FDG tracers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
∗ Corresponding author at: Department of Nuclear Medicine and PET, 1 Elizabeth Drive, Liverpool Hospital, Liverpool, New South Wales 2170, Australia.el.: +61 2 9828 3515; fax: +61 2 9828 3529.
E-mail address: [email protected] (M. Lin).
040-8428/$ – see front matter. Crown Copyright © 2010 Published by Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.critrevonc.2010.04.011
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bstract
Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality. Molecular imaging using positron emission tomographyPET) is now an integral part of multidisciplinary cancer care. In this review, we discuss the role of PET in CRC including well establishedndications in the assessment of recurrent disease and emerging applications such as initial staging, monitoring therapy efficacy and usingET for radiotherapy planning. With rapid advancement in imaging technology, we also discuss the future potential of combining PET andagnetic resonance imaging and the use of novel radiotracers.rown Copyright © 2010 Published by Elsevier Ireland Ltd. All rights reserved.
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eywords: Positron emission tomography; PET; FDG; Colorectal cancer; O
. Introduction
Colorectal cancer (CRC) is a major cause of cancer-relatedorbidity and mortality in developed countries. In 2006 thereere 412,900 new cases of CRC in Europe and responsi-le for 217,400 deaths [1]. In the United States, CRC is thehird most common cause of cancer mortality estimated in009 [2]. Over the last two decades, there has been an enor-ous growth in the literature demonstrating the benefits of
ositron emission tomography (PET) in many malignancies3] and is now an integral part of multidisciplinary cancerare. The initial results from the United States National Onco-ogic PET Registry of 22,975 studies in 21,419 patients from178 centres showed that physicians changed their intendedanagement in more than a third of cases in light of PETndings [4]. Since the basic principles and various oncologicpplications of PET were reviewed in this Journal recently5], the general principles of PET scanning will only be dis-ussed in brief. In this review, we shall focus on the role ofET in CRC.
. Positron emission tomography
.1. PET and PET-CT
PET detects pairs of photons emitted in opposite directionsollowing the annihilation of positron emitting radioisotopes.ET cameras record data in three dimensions and allow the
ocalisation of this process in vivo. The advent of combinedET and computed tomography (CT) scanners (PET-CT)llows the fusion of functional and anatomical information insingle scan with an improvement in diagnostic confidence
nd accuracy compared to PET and CT data viewed side byide, PET alone or CT alone [6–8]. As a result, PET-CT hasow largely replaced PET-only systems.
[Fluorine-18]-2-fluoro-2-deoxy-d-glucose (FDG) is aadiolabelled glucose analogue and is by far the most widelysed positron emitting radiopharmaceutical for PET. Becauseancer cells exhibit enhanced glycolytic metabolism, thisolecular process is depicted by mapping FDG uptake using
ET cameras. The degree of metabolic activity or FDGptake by tissue, expressed as a standardised uptake valueSUV), can also be quantitatively assessed and comparedetween studies (e.g. pre- and post-treatment). PET allows3
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unique insight into tumour biology and the correlation ofDG metabolism and tumour proliferative rates may in turne useful in determining prognosis in CRC [9].
.2. PET-CT colonography
There has been recent interest in combining PET-CTnd virtual colonography as an “all-in-one” staging modal-ty. By using pharmacologic bowel relaxation, rectal waternema to maintain bowel distension and PET imaging in therone position, Veit-Haibach and colleagues demonstrated alight improvement in the accuracy of staging using PET-CTolonography compared with PET and CT [10]. In 47 patientsith 50 lesions, the overall TNM stage was correctly assigned
n 74% of the patients using FDG PET-CT colonography and4% using CT and PET. Patients with incomplete conven-ional colonoscopy due to obstructing lesions may also benefitrom PET-CT colonography. In a small number of patientsith CRC (n = 13) that could not be traversed by optical
olonoscopy, PET-CT colonography detected 2 synchronousRC proximal to the stenosis [11]. The major advantage of
he procedure is that it could be performed without bowelreparation. Despite limited data showing its feasibility andotential utility, the precise role of PET-CT colonographys not well defined at this point in time and should not bedopted as standard protocol.
. Clinical applications
.1. Initial staging
The role of FDG PET in staging CRC is not wellstablished and is currently not recommended as a routinenvestigation [1]. While there is emerging evidence of incre-
ental benefit in addition to conventional modalities in rectalancer, its role in colon cancer remains controversial. Fur-hermore, the studies often comprised both colon and rectalancers from which subgroup analyses were not always car-ied out.
.1.1. Rectal cancerTumour stage is the strongest predictor of recurrence in
ectal cancer [12]. Accurate staging determines different ther-peutic options such as the type of surgery and the need for
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reoperative neoadjuvant therapy for downstaging. Transanalocal excision or transanal endoscopic microsurgery (TEMS)s usually undertaken for early rectal cancers and rectal resec-ion with total mesorectal excision (TME) as the preferredurgical option for more advanced tumours (mainly T2 or3). TME achieves maximum radial clearance for cancers
n the middle or lower third of the rectum and preopera-ive evaluation of tumour extent in relation to the mesorectalascia has gained particular importance. A positive circum-erential resection margin (CRM) is strongly predictive ofocal recurrence following surgery [12–15]. Magnetic res-nance imaging (MRI) has exquisite soft tissue definitionhat allows a detailed evaluation of the rectal wall, mesorec-al fascia, extent of local invasion and the likelihood of aumour-free CRM [16,17]. Endoscopic ultrasound (EUS) islso useful in local staging of rectal cancers [18]. Currently,ET is unlikely to contribute significantly towards determin-
ng the T-category of the primary tumour in addition to MRIr EUS due to its limited spatial resolution.
Where PET appears promising in staging rectal cancers isn the detection of lymph node and distant metastases. Lymphode involvement in rectal cancer is prognostic [14], however,he assessment by various imaging modalities remains a chal-enge. A meta-analysis (n = 90) evaluating CT, MRI and EUSn lymph node staging revealed sensitivities of 55%, 66% and7% respectively [18]. Assessment of lymph node involve-ent based on size criteria is unreliable and in one study,
o significant difference in size was found on MRI betweenenign and malignant lymph nodes [19]. On the other hand,unctional imaging with FDG PET may be useful and recenttudies have shown the benefit of PET in addition to con-entional staging in primary rectal cancer. In a study (n = 37)y Gearhart and colleagues, the addition of FDG PET-CTo spiral CT and transrectal ultrasound (TRUS) or MRIevealed discordant findings in 38% of patients, 50% of whomere upstaged, and the commonest finding was the detectionf unsuspected inguino-femoral or pelvic lymphadenopathy20]. Discordant findings were found to be significantly moreommon in patients with low-lying rectal cancers than thoseith mid or upper cancers (P = 0.0027). These discordantndings resulted in a change in planned management in 27%f patients. The largest series so far involved 83 patients allf whom were staged with abdominal and pelvic CT scan,RI or TRUS or both, as well as PET-CT [21]. A change in
umour stage occurred in 31% of patients after PET-CT andearly half the patients were upstaged by identifying unsus-ected systemic and lymph node metastases. All the casesown-staged by PET-CT were also proven to be accurateased on resected specimens and clinical follow-up. Over-ll PET-CT led to a high impact change of managementchange in treatment modality or intent) in 14% of patients.imilar results were found in other studies with smaller num-
er of subjects that used PET alone or combined PET-CTcanners [22–25]. However, in one series, the incrementalenefit of PET over multi-detector CT scan was reportedlyuch smaller [26]. Early experience with the use of con-tsrt
gy/Hematology 77 (2011) 30–47
rast enhancement in combined PET-CT studies suggestedurther diagnostic benefit may be gained when compared withon-enhanced PET-CT in depicting regional nodal status inectal cancer [27]. For detection of distant metastases, PETs highly accurate in detecting synchronous liver and lung
etastases and may reveal more extensive metastatic diseasehat precludes metastasectomy [23,28].
.1.2. Colon cancerPET has a high sensitivity for detecting the primary
umour in the colon ranging between 95% and 100%24,26,29–31]. In contrast, for lymph node staging, mosttudies have reported low sensitivity (29–43%) and highpecificity (56–96%) [23,24,29,31]. The high false negativeates are most likely due to a combination of limited spatialesolution of PET, high FDG activity in the primary tumournd physiologic tracer excretion in the bladder which canbscure detection of closely adjacent involved lymph nodes.ize of involved lymph nodes is also a factor. In a morphome-
ric study of colon cancer specimens, lymph nodes infiltratedy metastases averaged 5.9 mm in diameter and more than0% were less than 5 mm [32], which approaches the limitsf resolution of clinical PET systems. The accuracy of FDGET in nodal staging has not been shown to be superior to thatf multi-detector CT scan and may be of limited incrementalalue [24].
PET has been shown to be more sensitive in the detectionf distant metastases not recognized on conventional diagnos-ic modalities in a small number of patients with colon cancer23,29,31], in particular extra-hepatic distant metastases inatients who are potential candidates for metastasectomy23,24]. In a pre-selected group of patients (n = 100) with pre-perative serum CEA levels ≥10 ng/mL or equivocal findingsn CT scan for metastatic disease, the addition of PET-CThanged the treatment modality or extent of surgery in 27%atients with colorectal cancers [33].
Although the data is limited and consisted of a mixed pop-lation of colon and rectal cancer patients, there appeared toe potential incremental benefit with PET in only selectiveatients with colon cancer. PET is most useful in patients withuspected but inconclusive synchronous distant metastaticisease on conventional modalities. Routine PET scanningor the initial staging of colon cancer, currently, is probablyot justified.
.2. Staging of recurrent colorectal cancer
Recurrent CRC following curative resection is commonnd occurs in approximately 40% of patients; the most fre-uent sites are hepatic, pulmonary or loco-regional [34].etastasectomy of solitary hepatic or pulmonary lesions
nd resection of isolated local recurrence in CRC is poten-
ially curative. Previous reports have documented 5 yearurvival rates of 20–31% following resection of localecurrence [35,36] and 37–47% after hepatic metastasec-omy [37,38]. However a significant proportion of patients
M. Lin et al. / Critical Reviews in Oncolo
Fig. 1. (a) A 64-year-old man with previous right hemicolectomy for aT2N0M0 adenocarcinoma of the caecum 3 years ago presented with apresumed solitary hepatic metastasis in the right lobe of liver for potentiallycurative metastasectomy. Preoperative FDG PET scan for restagingdemonstrated intense focal uptake in segment VI/VII of the liver (arrow) aswell as a small focus of mildly increased FDG accumulation within a 9 mmlymph node in the medial left supraclavicular fossa (arrowhead) suspiciousfor extrahepatic metastases. Fine needle aspiration biopsy of the lymph nodeconfirmed metastatic adenocarcinoma thereby obviating futile surgery. In therest of the scan, there was normal FDG uptake in the base of brain, laryngeal
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ave unresectable disease at surgery or relapse within 1–2ears following resection, implying suboptimal preoperativeatient selection by conventional means [39]. The incre-ental benefit with the addition of FDG PET in restagingRC is well established, cost effective [40] and has mademajor impact on patient management mainly by identify-
ng further unexpected metastases or more extensive disease41–44]. FDG PET is an invaluable tool in recurrent CRC ands incorporated into management guidelines and diagnosticlgorithms [1,45,46].
.2.1. Evaluation of hepatic metastases for liveresection
FDG uptake in hepatic metastases from colorectal originas demonstrated on a single-slice PET scanner more than
wo and a half decades ago [47]. Since the initial observa-ion, there has been an abundance of literature examininghe use of PET in this group of patients. Two systematic
eta-analyses comprising 32 and 61 studies respectivelyemonstrated high diagnostic values of FDG PET in thevaluation of liver metastases [48,49]. The pooled sensitiv-ty and specificity of PET was 88% and 96.1% respectivelyor hepatic disease and 91.5% and 95.4% for extra-hepaticisease [48]. The sensitivity of PET for detecting liver metas-ases was superior to other imaging modalities including
RI on a per patient basis [49]. When compared with CT,he superiority of PET is in the detection of unsuspectedxtra-hepatic disease [44,48,50] (Fig. 1) and the yield ofET correlated with clinical risk scores [37,51]. For small
iver lesions (<1 cm), however, several recent studies havehown MRI with liver-specific contrast agents or dedicatedequences to be slightly more sensitive than PET-CT [50,52].he improved survival observed in patients screened withET prior to surgery reflects better patient selection [53,54].
retrospective analysis of 461 patients showed preoper-tive PET imaging was associated with a lower risk ofon-therapeutic laparotomy [55]. A recent phase III ran-omised, multicenter trial (n = 150) further underlined thetrength of PET by showing the addition of PET to CT-basedonventional work-up prior to hepatic resection in metastaticRC (mCRC) reduced unnecessary laparotomies from 45%
o 28% and avoided futile surgery in 1 out of every 6 patients56].
Several interesting observations have also been made inhe era of using PET for the assessment of CRC hepatic
etastases. In FDG PET-staged patients who undergo liveresection, early recurrence (<1yr) was observed predomi-antly in the liver whereas later recurrences (>1yr) occurredn extra-hepatic sites [57]. It has also been shown that SUV
uscles, rest of the hepatic parenchyma, spleen, and urinary tracer excretion.here was also prominent physiologic uptake in the lower abdomen in theigmoid colon. (b) Fused transaxial PET and CT images allowed preciseocalisation of FDG uptake to a small lymph node in the left supraclavicularossa providing the site for fine needle aspiration biopsy under ultrasounduidance.
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f hepatic metastases may be prognostic with significantlyonger survival for patients with lesions exhibiting a low SUV58,59]. This may have a potential for selection of high riskatients for more aggressive therapy based on PET. Finally,cheer and colleagues observed a significant increase in SUVf CRC hepatic metastases after resection of the primaryumour compared with patients without surgical or therapeu-ic intervention [60]. The change in SUV did not correlateith the size of lesions and a possible mechanism related to
oss of anti-angiogenic factors such as angiostatin producedy the primary tumour and a potential role for adjuvant anti-ngiogenesis therapy to prevent progression was suggested.
.2.2. Assessment of local recurrence for salvagereatment
Early studies have shown PET to be useful in identify-ng locally recurrent CRC [61] and to differentiate betweenecurrence and post operative inflammation/scar [62,63]. Aeta-analysis (n = 366) showed PET had an overall sen-
itivity of 94.5% and specificity of 97.7% for identifyingocal/pelvic recurrence [41]. PET is more sensitive than CTcans in detecting local recurrence, increases diagnostic con-dence in lesions deemed equivocal on anatomic imaging and
dentifies additional metastases [64–66]. However, inflamma-ory abdominal or pelvic lesions are known causes of falseositivity. Combined PET-CT results in an improvement inensitivity and specificity when compared with PET-alonetudies in the assessment of pelvic recurrences [67,68] andiagnostic accuracy may be further improved with PET-CTerformed with contrast enhancement [69]. In a recent studyomprising 93 patients with symptomatic residual structuralesions at various locations considered equivocal on conven-ional imaging, PET (97% of the patients underwent PET-CT)etected additional lesions in nearly 50% of subjects and ledo a high impact management change (i.e. a change in treat-
ent modality or intent) in 65% of patients [44]. Patientsith additional lesions on PET also had a significantly poorerrogression-free survival (P = 0.04). A previous surveyocumented similar results where there was a change in man-gement following PET in more than 60% of patients [42].
.2.3. Early detection of biochemical recurrence (risingerum CEA levels)
Serum carcinoembryonic antigen (CEA) elevation mayrecede detection of disease relapse by conventional meth-ds by a few months. Previously, serum CEA-directedecond-look laparotomies had low resectability rates due tonexpected metastatic disease especially when CEA levelsxceeded 11 ng/ml [70]. PET has been shown to be ableo identify the site of suspected recurrent CRC in patientsith an unexplained rise in CEA levels [65,71]. With normalr equivocal radiologic findings and rising serum CEA lev-
ls, the sensitivity and positive predictive value of PET areeportedly 87–100% and 89–96% respectively in detectingecurrent malignancy [72–74] (Fig. 2). A significant correla-ion was found between serum CEA levels and PET derived(icc
gy/Hematology 77 (2011) 30–47
umour volumes reflecting tumour burden [75]. Some authorsuggest a cutoff value for unexplained serum CEA > 10 ng/mls an indication for FDG PET scanning [74]. PET may alsollow earlier disease detection preceding subsequent rise inerum CEA levels in patients with clinical or radiologicaluspicion for tumour recurrence [76].
.2.4. To identify peritoneal carcinomatosisPeritoneal recurrence in mCRC is a known cause for false
egative findings on FDG PET scans [43,64,65,72,74]. PETay also lead to an underestimation of the extent of peri-
oneal involvement [77] and lower sensitivities in mucinousdenocarcinomas due to hypocellularity [64]. When com-ared with CT scan, some studies have documented higherensitivity with PET in CRC [65,77] while others have shownqually poor performance [78]. Although certain diagnosticatterns of peritoneal carcinomatosis have been describedn PET [79] and superior accuracy with combined PET-CT80], the number of CRC patients studied so far using PETas been small. PET currently cannot replace laparoscopy forxclusion of peritoneal carcinomatosis.
.3. Prognostication and evaluation of treatmentesponse
Monitoring therapy response is essential to guide optimalndividualised cancer treatment. Early identification of treat-
ent failure allows a switch to an alternative managementtrategy with the hope of achieving better outcomes. On thether hand, low risk patients who demonstrate early responseay qualify for less aggressive regimen avoiding potential
nnecessary treatment related toxicities and complicationsnd may be cost saving. Currently, the assessment of thera-eutic efficacy in solid tumours is based on changes in sizef lesions measured on anatomical imaging (e.g. Responsevaluation Criteria in Solid Tumours [RECIST]) [81] whichave well recognized limitations. A tumour that has reducedn size may contain viable malignancy, and conversely aesidual mass may represent post-therapy changes such asnflammation, fibrosis or necrosis with no viable malignantells. Since metabolic changes precede volumetric changes,maging tumour bio-markers using PET as a surrogate mea-ure for therapy response should be more sensitive and morepecific. A favourable therapeutic response is often governedy the degree of reduction in SUV. However, the thresholdf reduction that gives the best predictive value is variablend mainly relies on post-hoc analyses. Regardless of theET techniques used in response evaluation (e.g. qualitative,emi-quantitative or quantitative), standardisation of scan-ing parameters, time points at which responses are measurednd interpretative criteria are paramount to minimise inter-bserver variability. The recent publication of PERCIST
PET Response Criteria in Solid Tumors) 1.0 criteria is anmportant starting point and represents a draft framework thatan be used for clinical studies [82]. In locally advanced rectalancer, there is mounting evidence of the value of FDG PET
M. Lin et al. / Critical Reviews in Oncology/Hematology 77 (2011) 30–47 35
Fig. 2. (a) A 55-year-old man with previous subtotal colectomy for an obstructed T4N2M0 moderately differentiated adenocarcinoma of the transverse colon.Post-operative carcinoembryonic antigen (CEA) level was 4.9 ng/ml. During adjuvant FOLFOX (fluorouracil, leucovorin and oxaliplatin) chemotherapy, theserum CEA level rose to 15 ng/ml. A diagnostic CT scan showed two ill-defined hypodense lesions in the spleen which were deemed equivocal for metastases.F (arrowT l FDG ur in the l
afiap
3
acpa
dpo1oats
DG PET scan demonstrated two foci of intense FDG uptake in the spleenransaxial CT, PET and fused PET-CT images demonstrating intense focaevealed a subtle hypodensity. There was physiologic urinary tracer activity
s a prognostic marker and in predicting pathologic responseollowing neoadjuvant treatment. PET is also useful in mon-toring therapy response following local ablative treatmentsnd PET may be able to tailor neoadjuvant chemotherapyrior to metastasectomy and in the palliative setting.
.3.1. Neoadjuvant therapy for rectal cancerPathologic complete response following neoadjuvant ther-
py is a good prognostic factor in locally advanced rectalancers. Where less aggressive surgery (such as sphincter-reserving operations) may be contemplated in responders,n escalation of treatment (such as increasing the radiation
laap
s) highly suspicious for metastases, which were confirmed at surgery. (b)ptake at the site of the splenic lesion which on concurrent CT scan, only
eft kidney.
ose) may potentially be appropriate in non-responders. Theotential of FDG PET in assessing the therapeutic effectf chemo-radiation for rectal cancer was raised in the early990s [63]. A number of studies have now shown the abilityf PET to predict pathologic response in the primary tumour,lthough most of them are post-hoc analyses and variable inheir methodologies in terms of time points at which PETcans are performed (mostly between 2 and 6 weeks fol-
owing neoadjuvant treatment), metabolic response criteriand reference standards [83–88]. SUV reduction as earlys 12 days after chemo-radiation has also been shown toredict tumour regression grade (P < 0.0001) [89]. On the
3 Oncolo
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3
oa(iatIlisebddh
imndlocmdbtairpcsmdt
FwwCt
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6 M. Lin et al. / Critical Reviews in
ther hand, the sensitivity for assessing response in regionalymph nodes is disappointing [85] and PET is not accuraten predicting tumour clearance from the mesorectal fasciaollowing neoadjuvant therapy [87]. Metabolic response onET can also predict survival [90,91]. In the study by Capircind colleagues, 5-year overall survival was 91% in patientsith a negative PET performed 7 weeks after chemoradi-
tion and 72% in those with a positive PET (P = 0.024)90]. Post-radiation effects did not seem to compromise PETcan interpretation for therapy response amongst experiencedeaders [92]. Despite the heterogeneity of the studies, PETppears promising and most likely has a role to play inhe assessment of response to neoadjuvant therapy. Whetherisk adapted strategies (either escalation or de-escalation ofreatment) based on metabolic response identified on PETcanning improves clinical outcomes can only be borne outn future randomised controlled trials.
.3.2. ChemotherapyThere has been significant progress in the management
f mCRC with the incorporation of novel targeted therapiesgainst angiogenesis and epidermal growth factor receptorEGFR). The vascular endothelial growth factor (VEGF)nhibitor bevacizumab and EGFR antagonist cetuximab inddition to chemotherapy are gradually being adopted inreatment regimens following promising results from phaseII trials [93]. Some of these agents are cytostatic and may notead to a substantial reduction in tumour size and responses often underestimated by anatomical methods [94]. Patientelection is important in order to avoid futile treatment. Forxample, K-ras mutation status determines who would notenefit from cetuximab. A recent study using dynamic PETata and FDG kinetics also demonstrated the potential to pre-ict angiogenesis related gene expression that may furtherelp individualize treatment [95].
Several small studies investigated the use of FDG PETn the setting of neoadjuvant therapy and colorectal liver
etastases prior to hepatic resection (Table 1). Followingeoadjuvant treatment, most studies demonstrate a significantecrease in the sensitivity and accuracy of PET in detectingiver metastases [96–99]. In one study [97], the sensitivityf PET-CT following neoadjuvant chemotherapy was 49%ompared to a sensitivity of 93.3% in patients without treat-ent (P < 0.0001). The reasons for these findings include a
ecrease in the size of metastases following chemotherapyeyond the spatial resolution of PET [100], downregula-ion of the glycolytic enzyme hexokinase of tumour cellsnd compounded by the high physiologic FDG activityn normal hepatic parenchyma [96]. Complete metabolicesponse is therefore an unreliable predictor for completeathologic response [98] and the decision whether to pro-eed to liver resection or to determine the extent of surgery
hould not solely rely on PET findings. However, PETay have a prognostic role. In a recent study (n = 40),isease-free survival was predicted by metabolic responseo FOLFOX (fluorouracil, leucovorin and oxaliplatin) or
wpa
gy/Hematology 77 (2011) 30–47
OLFIRI (fluorouracil, leucovorin and irinotecan) with orithout bevacizumab prior to liver resection [101]. Patientsho did not demonstrate a response to chemotherapy on PET-T had a 3.8 times faster rate to disease recurrence compared
o patients with a response.There is limited data on the use of FDG PET in the
valuation of response to palliative chemotherapy in mCRCTable 1). In an early study by Findlay et al. [102], a reduc-ion in tumour to liver uptake (T/L) of ≥15% on PET at–5 weeks after the initiation of 5-fluorouracil (5-FU) basedhemotherapy had a sensitivity and specificity of 100% and5% respectively in predicting tumour response. Paradox-cally, they also observed a marked increase in T/L ratiost 1–2 weeks following treatment in lesions that showed aesponse later on and labelled it a “flare phenomenon”—annflammatory reaction due to infiltration of macrophagess a response to tumour cell kill. However, this was notvident when PET was performed very early at 72 h aftersingle infusion of chemotherapy [103]. The prognostic
spects of PET following chemotherapy have also beenxamined. Using quantitative techniques and FDG kineticarameters, Dimitrakopoulou-Strauss et al. were able to pre-ict survival and stratify patients into short (<1 yr) and long>1 yr) survival classes following second-line chemotherapyomprising 5-FU, folinic acid and oxaliplatin [104]. For clin-cal applicability, more simplified SUV measurements wereound to be reliable [106]. Although there was a strong cor-elation between metabolic and radiological responses, instudy using the European Organisation for Research andreatment of Cancer (EORTC) criteria [107] for assessingarly metabolic response, PET was not found to be pre-ictive of long-term outcomes [108]. However, this coulde a reflection of the response criteria used which may notave given the best predictive value specifically in mCRC.he incorporation of PET to assess chemotherapy response
n future clinical trials allow an early selection of patientsho are refractory to chemotherapy regimens and a switch to
lternative treatments with the aim of improving outcomes.
.3.3. Local ablative therapyIn patients where surgical resection of liver metastases
s not feasible such as unfavourable tumour location, extentr patient co-morbidities, local ablative therapy (radiofre-uency ablation [RFA], cryosurgery ablation [CSA], LASERnduced thermotherapy [LITT], transarterial chemoemboli-ation [TACE] or selective internal radiation therapy [SIRT]sing yttrium-90 [90Y] labelled resin or glass microspheres)s an alternative treatment option for local control. Anatom-cal modalities are often unable to differentiate betweenesidual tumour and peri-lesional post therapy changes andunctional imaging with FDG PET may be advantageousTable 2).
An early study [109] comprising 23 patients who under-ent RFA or CSA of colorectal liver metastases, PETerformed within three weeks post-procedure had a neg-tive predictive value of 100% (51 of 56 lesions became
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Table 1FDG PET and monitoring chemotherapy response.
Author (Ref) N METS PET Regimen Timing of PET Parameters Reference standard Criteria Main results
Goshen [94] 7 Liver PET-CT FOLFOX andbevacicumab
Baseline and after 4cycles
Visual Histopathology Complete or partialresponse, stable orprogressive disease
PET findings correlated betterthan CT with pathology andmore accurately at predictingtumour necrosis
Akhurst [96] 42 Liver PET Neoadjuvantfluorouracil-basedchemo
Preop Visual, SUV Histopathology Lesion detection 15/41(37%) and 16/69 (23%)lesions in patients with orwithout chemotherapy notdetected by PET.Phosphorylating activity ofhexokinase significantlylower after chemotherapy
Lubezky [97] 75 Liver PET-CT NeoadjuvantFOLFOX/FOLFIRI± Bevacicumab
Baseline and Preop Visual Histopathology reports Lesion detection Sensitivity = 49% withneoadjuvant therapySensitivity= 93.3% withoutneoadjuvant treatment(P < 0.0001)
Tan [98] 14 Liver (withCMR)
PET-CT Variouschemotherapy± bevacicumab/cetuximab
Baseline and Preop Visual Histopathology Complete pathologicresponse
Only 5/34 lesions (15%) andin 3/14 patients (21%) hadcomplete pathologic responsedespite PET showing CMR
Adie [99] 74 Liver PET-CT Various neoadjuvantchemotherapyregimens
Preop Visual Intraoperativeexamination andultrasoundHistopathology
Accurate PET-CT scans Accurate scans in 29%patients (n = 6) with chemo vs71% (n = 28) without chemo(p = 0.06). 1.7 vs 0.7 lesionsmissed (chemo vs no chemo)
Takahashi [100] 7 Liver PET andPET-CT
Neoadjuvantfluorouracil-basedchemo
Baseline and Preop Visual Histopathology Viable lesion detection Sensitivity = 100% and 17%in evaluating viability ofhepatic mets >2 cm and<2 cm respectively followingneoadjuvant therapy
Small [101] 40 Liver PET-CT NeoadjuvantFOLFOX/FOLFIRI± Bevacicumab
Before and afterchemo
Visual OS, DFS Complete or partialresponse, stable orprogressive disease
Response on PET-CT notpredictive of OS butpredictive of DFS
Findlay [102] 14 Liver (>3 cm) Non dedicatedPET
5-fluorouracil± interferon-�
Baseline, 1–2 weeks,4–5 weeks
Tumour to liver (T/L)ratio, SUV
Tumour dimensions onCT/MRI at 12 weeks.WHO criteria
Tumour dimensions T/L reduction of 15% at 4–5weeks: Sensitivity = 100%Specificity = 75%. SUV lessreliable.
Bender [103] 6 Liver and lung PET Single infusion 5-fluorouracil + folinicacid
Baseline and 72h SUV Tumour dimensions onCT or MRI at-6 weekintervals WHO criteria
Change in SUV Responding mets—22%reduction in SUV
Dimitrakopoulou-Strauss[104]
20 Liver (93%) Dynamic PET 2nd line5-fluorouracil, folinicacid, oxaliplatin
Baseline, after 1cycle, after 4 cycles
SUV, kinetics, fractaldimensions
Survival Short survival class(<1yr)
CCR:SUV after 1cycle = 62%, SUV after 4cycles = 69%, kinetic dataafter 1 and 4 cycles = 78%
Long survival class(>1yr)
Baseline SUV and fractaldimensions also prognostic
38 M. Lin et al. / Critical Reviews in Oncolo
Tabl
e1
(Con
tinu
ed)
Aut
hor
(Ref
)N
ME
TS
PET
Reg
imen
Tim
ing
ofPE
TPa
ram
eter
sR
efer
ence
stan
dard
Cri
teri
aM
ain
resu
lts
Dim
itrak
opou
lou-
Stra
uss
[105
]28
Liv
er(9
4%)
Dyn
amic
PET
2nd
line
5-flu
orou
raci
l,fo
linic
acid
,oxa
lipla
tin
Bas
elin
e,af
ter
1cy
cle,
3m
onth
sSU
V,f
ract
aldi
men
sion
sC
linic
alre
spon
se,W
HO
crite
ria
Prog
ress
ive
(PD
)or
stab
ledi
seas
e(S
D),
part
ialr
espo
nse
CC
Rfo
rba
selin
eSU
Van
dfr
acta
ldim
ensi
ons:
93%
for
PD,6
0%fo
rSD
.B
asel
ine
SUV
<4.
6pr
edic
tsno
n-re
spon
ders
deG
eus-
Oei
[106
]50
Liv
eran
dlu
ng(9
1%)
Dyn
amic
PET
Var
ious
chem
ore
gim
ens
Bas
elin
e,2
mon
ths,
6m
onth
sM
RG
lu,S
UV
OS,
PFS
Frac
tiona
lcha
nges
ingl
ucos
em
etab
olis
mSi
gnifi
cant
corr
elat
ion
ofM
RG
luan
dSU
V.
Are
duct
ion
inM
RG
luof
>65
%an
dSU
Vof
>20
%at
2m
onth
spr
edic
tive
ofO
S
Bys
trom
[108
]51
Liv
er,l
ung,
lym
phno
des
PET
Irin
otec
anba
sed
regi
men
Bas
elin
e,af
ter
2cy
cles
Vis
ual,
SUV
Rad
iolo
gica
lres
pons
e(R
EC
IST
crite
ria)
ever
y4c
ycle
s,T
TP,
OS
EO
RT
Ccr
iteri
afo
rm
etab
olic
resp
onse
PPV
=71
%,N
PV=
81%
com
pare
dw
ithra
diol
ogic
alre
spon
se.N
osi
gnifi
cant
corr
elat
ion
betw
een
met
abol
icre
spon
sean
dT
TP
orO
S
Met
s:si
tes
ofm
etas
tatic
dise
ase,
CM
R:c
ompl
ete
met
abol
icre
spon
se,C
CR
:cor
rect
clas
sific
atio
nra
tes,
MR
Glu
:met
abol
icra
teof
gluc
ose,
OS:
over
alls
urvi
val,
DFS
:dis
ease
free
surv
ival
,PPV
:pos
itive
pred
ictiv
eva
lue,
NPV
:ne
gativ
epr
edic
tive
valu
e,ch
emo:
chem
othe
rapy
,TT
P:tim
eto
tum
our
prog
ress
ion,
FOL
FOX
:5-
fluor
oura
cil,
leuc
ovor
in,o
xalip
latin
,FO
LFI
RI:
5-flu
orou
raci
l,le
ucov
orin
,iri
note
can,
and
Preo
p:pr
ior
tohe
patic
rese
ctio
n.
pmbr(spa(IiwAupph[e6
twlACimDFaisorMdets
3
(remaptlrMpt
gy/Hematology 77 (2011) 30–47
hotopaenic on FDG PET) during a follow up period of 16onths. Similar high specificities have also been achieved
y other investigators [110–112]. PET also detected recur-ence and residual tumour earlier than conventional follow-upmainly CT scan and serum CEA levels) in several smalltudies [109–115]. Hence PET following initial RFA mayrovide an early signal to repeat ablation and guide ther-py by pinpointing the focus of enhanced metabolic activityi.e. viable malignancy) in a previously treated area [116].n a recent study (n = 16), both PET-CT and MRI had sim-lar accuracies for detecting local tumour progression andere significantly better than PET alone (P < 0.008) [117].lthough an early assessment (within 2 days following RFA)sing PET seems feasible in a small pilot study [118] and hasotential advantages in identifying early treatment failure,ost-RFA inflammation/tissue regeneration at this time pointas been observed which can also confound interpretation114]. To get round this, some have suggested either a veryarly PET scan within 12–24 h post RFA or alternatively after–8 weeks as the best time points [120].
Liver metastases derive most of their blood supply fromhe hepatic artery. Selective internal radiation therapy (SIRT)ith intra-hepatic arterial administration of radioactive 90Y
abelled resin (SIRTEX Medical, North Ryde, Sydney,ustralia) or glass (TheraSphere, MDS Nordion, Ottawa,anada) microspheres aims to deliver high doses of ion-
sing beta-radiation to hepatic metastases selectively whileinimising radiation dose to normal hepatic parenchyma.espite a relatively small number of patients studied so far,DG PET has consistently been shown to be a more accuratend sensitive indicator of treatment response than anatomicmaging where there may not be a significant change in lesionize due to tumour necrosis, cystic degeneration or haem-rrhage following SIRT [121–125]. Using SUV, metabolicesponse can be measured semi-quantitatively [124–127].
ore recently, Flamen and colleagues were able to pre-ict metabolic response during pre-therapeutic work up bystimating the dose delivery to the tumours using a combina-ion of CT, Tc99m-labeled macroaggregated albumin (MAA)cintigraphy and FDG PET data [128].
.4. Radiotherapy planning
Incorporating PET data in radiation therapy planningRTP) seems intuitive. The advantages include more accu-ate and less variable active tumour volume determination,ncompassing unsuspected regional metastases in the treat-ent field, avoiding irradiation of non-malignant anatomical
bnormalities, and delineating tumour burden allowing doseainting (varying radiation doses to different regions of theumour). While benefits have been shown in non-small cellung and oesophageal cancers [129], there is a paucity of data
egarding the use of PET in RTP in rectal cancer (Table 3).ost PET-CT scans performed for the purposes of RTP areerformed in the radiotherapy treatment position with posi-ion fixation devices such as a belly board. A few small studies
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Table 2FDG PET and local ablative therapy.
Author (Ref) N (CRC) PET Therapy Timing of PET PET criteria Follow-up Reference standard Main results
Lagenhoff [109] 23 (23) PET CSA (n = 17)RFA (n = 6)
≤3 weekspost-treatment
Visual 16 months PET, CT, CEA NPV = 100%, PPV = 80%. PET detectedrecurrent malignancy earlier than CT
Donckier [110] 17 (11) PET RFA Baseline, 1 week, 1,3 monthspost-treatment
Visual 11 months PET, CT, Histopathology NPV = 100% (13/13), PPV = 100% (4/4)for local recurrence. PET superior to CT inearly detection of residual tumour
Anderson [111] 13 (8) PET RFA Pre and post RFA Visual Not specified Clinical, PET, CT,MRI PPV = 100% (11/11 lesions). PET superiorto MRI/CT in detection ofrecurrence/residual tumour
Joosten [112] 43 (43) PET CSA (n = 17)RFA (n = 6)
≤3 weeks posttreatment
Visual CSA-26 months, RFA-25months
PET, CT, CEA NPV = 100%, PPV = 88%. PET detectedrecurrent malignancy earlier than CT
Blokhuis [113] 15 (11) PET RFA Post RFA Visual 16.8 months Not specified PET identified local recurrence earlier thanCT (6.8 vs 9.8 months) following RFA
Veit [114] 11 (11) PET-CT RFA Baseline, 2 days Visual, SUV 11 months Histopathology, allimaging, clinical, CEA
Sensitivity and accuracies for residualtumour = 65% and 68% for PET/PET-CT,44% and 47% for CT alone
Travaini [115] 9 (7) PET-CT RFA 1 week, 1, 3, 6, 9months
Visual 9 months PET-CT, multi-detectorCT
PET superior to CT in early detection oflocal treatment failure in all cases
Kuehl [117] 16 (16) PET-CT RFA Baseline, 24 h, 1, 3, 6months then every 6months
Visual, SUV 22 months Histopathology, CT,clinical
PET-CT significantly better than PETalone for detecting LTP
No significant differences betweenPET-CT and MRI
Khandani [118] 8 (5) PET-CT RFA 2–41 h Visual 3–16 months Follow-up PET Infrequent inflammatory uptake at RFAsite of liver metastases on early PET
Denecke [119] 21 PET LITT Suspected residual orrecurrent disease
Visual, SUV >12 months Histopathology, CT,MRI, clinical
SUVmax of ablated lesions of 4.2discriminates partial and completeablation-Accuracy = 94%Overall NPV = 96%
Wong [121] 8 (8) PET SIRT(glass) Baseline, 3 month Visual 3 months PET, CT or MRI, CEA PET more sensitive in detecting responsethan CT/MRICorrelated better with CEA
Properl [122] 23 (12) PET or PET-CT SIRT(resin) Baseline, 3 month Visual 3 months PET, CT, tumour markers PET more sensitive in detecting responsethan CT
Bienert [124] 5 (4) PET-CT SIRT(resin) Baseline, 1 and 3months
Visual, SUV 22 months Response = SUVreduction of 20%
Metabolic changes more accurate thananatomical changes
Szyszko [125] 21 (10) PET SIRT(resin) Baseline, 6–8 weeks Visual, SUV 6–8 weeks PET, CT(RECIST),tumour markers
PET more sensitive in detecting responsethan CT. Significant reduction in SUVfollowing SIRT
Wong [126] 27 (27) PET SIRT(glass) Baseline, 3 months Visual, SUV 3 months PET (Visual vssemi-quantitative)
SUV of total liver uptake correlates withvisual analyses for response (r = 0.75)
Wong [127] 19 (10) PET SIRT(resin) Baseline, 3 months Visual, SUV 3 months PET (Visual vssemi-quantitative)
SUV of total liver uptake correlates withvisual analyses for response (r = 0.72)
Flamen [128] 8 (8) PET-CT SIRT(resin) Baseline, 6 weeks TLG 6 weeks PET response Simulated median absorbed dose = 20 Gyand 46 Gy in poor (<50%TLG change) andgood (>50%TLG change) responders
N (CRC): total number of patients (patients with colorectal cancer), CSA: cryosurgery ablation, RFA: radiofrequency ablation, CEA: carcino-embryonic antigen, LTP: local tumour progression, PPV: positivepredictive value, NPV: negative predictive value, LITT: LASER induced thermotherapy, SIRT: selective internal radiation therapy, and TLG: total lesion glycolysis.
40 M. Lin et al. / Critical Reviews in Oncology/Hematology 77 (2011) 30–47
Table 3PET and radiotherapy planning (RTP) in rectal cancer.
Author (Ref) N Method Results and conclusions
Ciernik [130] 6 Prone or supine PET-CT GTV increased in 3 patientsMean increase of GTV of 50%
Ciernik [131] 11 Prone PET-CT with belly boardAutomated region growing with fixedthreshold
Good correlation between BTV and CT based GTVGood correlation between PET and CT derived PTV
Patel [132] 6 Prone PET-CT with belly board Greater inter-observer agreement of GTVQualitative. FDG and FLT. No difference between FDG and FLT derived tumour volumes
Anderson [133] 23 20 rectal cancer, 3 anal cancer PET detected distant metastases in 25% rectal cancer patients.Prone PET-CT with belly boardQualitative
Radiation treatment plan changed in 26%Change in PTV in 17% patientsMean PET-GTV < Mean CT-GTV (92 cm3 vs 100 cm3)
Bassi [134] 25 Prone or supine PET-CT with knee fixdevice
Change in stage or treatment intent in 16% (4/25)
Fixed threshold methodPET-CT GTV and PET-CT CTV significantly greater than CT-GTV(25% increase) and CT-CTV
Paskeviciute [135] 36 Prone PET-CT with belly boardVisual, SUV > 2.5
Mean PET-CT-GTV vs Mean CT-GTV (62 cm3 vs 163 cm3)In 46% (n = 16) patients, PET-CT resulted in modification ofCT-PTV due to geographic miss. 8% (n = 3) patients changed fromdefinitive to palliative management
Roels [136] 15 Prone PET-CT with belly board FDGand FLT or FMISO
FDG and FLT TV show good spatial correspondence
Pre and post chemoradiationLess reliable for FMISO
Roels [137] 15 Prone PET-CT with belly boardBefore, during, and after preoperativechemoradiation
Substantial change of GTVMean mismatch of 50% of PET and MRI tumour volume
G ic targefl
hbhtTPa
3
iaruifrfipsrp9watop
3
anCsJuiatgi(nacgwogf
3
PET and MRI
TV: gross tumour volume, PTV: planning target volume, BTV: biologuorodeoxythymidine, and FMISO:18F-fluoromisonidazole.
ave shown the detection of unsuspected metastatic diseasey PET and thereby altering management [133,134]. Othersave documented changes in tumour volume delineation withhe incorporation of metabolic information in RTP [134,135].he use of PET in RTP is experimental and whether usingET-CT data for RTP improves clinical outcomes is unknownnd larger studies are needed.
.5. Post-treatment surveillance
Surveillance in CRC in order to detect early relapses a contentious topic especially with regards to the mostppropriate imaging modality [138]. Earlier detection ofecurrences in asymptomatic patients by systematic follow-p allows potentially more curative resections [139] andmproved outcomes. This supports the idea of an intensiveollow-up programme, perhaps in selected patients at highisk of relapse. While there is emerging evidence of bene-ts using FDG PET in routine surveillance of asymptomaticatients with other cancers [140,141], there is very limitedupportive data in CRC [142,143]. In one study (n = 130),ecurrences were detected after a shorter time interval inatients who were followed-up with the addition of PET atand 15 months after initial surgery compared with patientsho underwent conventional follow-up [143]. The authors
lso reported a higher number of curative surgical interven-ions in the PET group. Currently, due to sparse data, the usef FDG PET in routine surveillance of CRC in asymptomaticatients is not recommended but may have a future role.
Wt
t volume, CTV: clinical target volume, TV: tumour volume, FLT: 18F-
.6. Screening
There is strong evidence that screening reduces mortalitynd incidence of CRC [144]. The ideal screening test is cheap,on-invasive and detects cancer early in high-risk individuals.RC and adenomatous polyps have been detected in various
creening programs incorporating FDG PET [145–148]. In aapanese nationwide survey involving 50,558 subjects whonderwent screening with PET or PET-CT, CRC was detectedn 102 (0.2%) and predominantly in men above 50 years ofge [149]. However, it is debatable whether PET is cost effec-ive when applied to unselected general population screeningiven the significant number of false negative and false pos-tive PET findings [148,150–152]. In one screening seriesn = 2911), PET detected 7 cases of CRC and was falselyegative in 28 asymptomatic individuals [148]. There werelso 104 false positive cases out of 111 in the colorectal regionomprising predominantly a misinterpretation of physiologicastrointestinal uptake, inflammatory lesions and 11 casesith benign adenomas. At this stage, screening with PET isf unproven efficacy. Whether it has a future role in more tar-eted populations, for example in first degree relatives with aamily history of CRC, using PET-CT, remains speculative.
.7. Incidental colonic FDG uptake
Physiologic colonic FDG uptake is common on PET scans.hile diffuse uptake can be seen as a normal variant or due
o a benign aetiology such as inflammation, focal colonic
Oncolo
uoboust[
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Fdarsaa
M. Lin et al. / Critical Reviews in
ptake may indicate a more sinister pathology. The majorityf cases of incidental focal colonic FDG uptake are causedy a synchronous adenoma or carcinoma which is uncoveredn further evaluation when the bowel uptake was deemed an
nusual site for metastatic disease [154–156] (Fig. 3). Theensitivity of FDG PET to detect pre-malignant adenoma-ous polyps correlated with size [146] and grade of dysplasia157]. Non-pre-malignant lesions such as hyperplastic polyps[fpi
ig. 3. (a) A 58-year-old man with newly diagnosed non-small cell lung cancer unemonstrated intense FDG uptake in the right pulmonary hilum encasing the bronlso mild ill-defined uptake surrounding this consistent with associated atelectasisectosigmoid junction (arrowhead). There was physiological urinary FDG accumulaagittal PET and CT images demonstrated intense FDG uptake corresponded to circsecond malignancy. Colonoscopy and biopsies revealed a synchronous adenocar
nterior and inferior to the colorectal tumour.
gy/Hematology 77 (2011) 30–47 41
o not tend to accumulate FDG [29]. The intensity of FDGptake in terms of maximal SUV was unable to discriminateetween malignant, pre-malignant and benign lesions [155].owever, the specificity is improved with combined PET-CT
7] (Table 4) and incidental focal colonic uptake deservesurther confirmatory investigations to exclude a malignantathology in appropriate patients whose management for thendex cancer is not palliative.
derwent a PET-CT scan for staging. Maximum intensity projection imagechus intermedius (arrow) at the site of the primary malignancy. There wasand inflammation. There was unsuspected focal intense FDG uptake at thetion in the bladder below this and tracer excretion in both kidneys. (b) Fusedumferential mucosal thickening at the rectosigmoid junction suspicious forcinoma. There was intense physiologic FDG excretion in the bladder just
42 M. Lin et al. / Critical Reviews in Oncology/Hematology 77 (2011) 30–47
Table 4PET-CT and incidental focal bowel uptake.
Author (Ref) N Population Incidental boweluptake (%)
Diagnosis confirmed (%) Pre-malignantpolyp (%)
Carcinoma (%) Other malignancy PPV
Kamel [153] 3281 Cancer (2836)non-oncologic(445)
98 patients (3%) 69/98 patients (70%) 27 (39%) 9 (13%) 52%
Israel [155] 4390 Cancer 58 patients (1.3%) 28/58 patients (48%) 9 (32%) 4 (14%) 2 (Mets) 54%Even-Sapir [156] 2360 Cancer 33 patients (1.4%) 29/39 lesions (74%) 7 (24%) 11 (38%) 2 (Mets, NHL) 69%Gutman [158] 1716 Cancer 45 patients (2.6%) 20/45 patients (44%) 10 (50%) 3 (15%) 65%Hemandas [159] 110 Cancer 10 patients (9%) 7/10 patients (70%) 7(100%) 100%Lee* [160] 2916 Cancer 85 patients (2.9%) 44/85 patients (52%) 32 patients with
true positivefindings
73%
Lee [161] 1665 Cancer 62 patients (3.7%) 40/67 lesions (60%) 12 (30%) 10 (25%) 1 (NHL) 58%
rapolateP metasta
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* Number of patients with carcinoma and adenoma cannot reliably be extPV: positive predictive value, NHL: Non-Hodgkins lymphoma, and Mets:
. Future
.1. PET-MR
Technology is advancing at a tremendous pace. As CTecomes a constant neighbour of PET, new partnershipsuch as combined PET-MRI are making the transition fromresearch tool into clinical practice [162]. The notion of
uperimposing PET and MRI data in CRC was first sug-ested by Ito and colleagues in 1992 [63]. Where PET-CTcans are acquired sequentially, PET-MRI allows simulta-eous acquisition and temporal correlation of both sets ofata thereby improving spatial correlation by eliminatingotion artefact as a result of patient and organ movement.he strengths of such “one stop” multimodality imagingxtend beyond simply superimposing anatomical and func-ional images but also allowing simultaneous acquisitionf dynamic quantitative PET and functional MRI data inssessing tumour metabolism, perfusion and viability. Theotentially attractive clinical applications would include pre-ise therapy response assessment and treatment planning163]. The future may also see the combination of hybriduclear medicine and optical imaging systems [164].
.2. Non-FDG tracers
While FDG is the stalwart of PET, other molecularathways are being targeted using non-FDG tracers anday be complementary to FDG. 18F-fluoro-3′-deoxy-3′-
-fluorothymidine (FLT) has been investigated as a morepecific radioisotope for cellular proliferation. Imaging withLT potentially leads to fewer false positives since FDGptake can be due to local inflammation post-treatmentnd FLT specifically reflects cellular proliferation. However,
n a recent small study of rectal cancer patients (n = 10)ho underwent long course neoadjuvant chemoradiation,he degree of change in FLT uptake at 2 weeks after initia-ion and completion of neoadjuvant therapy did not correlate
iuvc
d from the data presented.ses.
ith histopathological tumour regression [165]. Similar dis-ppointing results have been found with the radiolabelledmino acid tracer carbon-11 methyl-l-methionine (MET)166]. These reports suggested that the reduction in tracerptake following therapy may reflect impaired tracer trans-ort rather than correlate with tumour cell viability.
Tumour hypoxia is increasingly recognised as onef the negative factors which impacts on the effec-iveness of chemotherapy and radiotherapy. Although8F-fluoromisonidazole (FMISO) is the most studiedypoxic tracer for PET imaging, it has limitations dueo prominent non-tumoural bowel uptake and may note optimal for rectal cancer. 60Cu-diacetyl-bis (N4-ethylthiosemicarbazone)(60Cu-ATSM) may be a suitable
lternative. In a pilot study of 17 patients with rectal cancers,atients with hypoxic tumours as depicted by 60Cu-ATSMET, were less responsive to therapy and had a worse prog-osis [167].
. Conclusions
The role of PET in CRC continues to evolve. While it isell established in the assessment of recurrent and residualRC and in patients prior to potential curative metastasec-
omy, the benefits of FDG PET in particular for staging inectal cancer, in the assessment of therapy efficacy as well asroviding early prognostic information in patients receivingeoadjuvant treatment are emerging. PET also has the poten-ial to assist in planning radiotherapy. FDG PET performedor indications other than CRC can detect incidental focalolonic uptake which has a significant rate of pre-malignancynd malignancy that warrants further investigations. With thencreasing appreciation and understanding of the underly-
ng molecular processes in oncogenesis, functional imagingsing PET and different radiopharmaceuticals will enable inivo assessment of tumour biology that would allow clini-ians to target, individualise and monitor therapy.
Oncolo
R
M
R
M. Lin et al. / Critical Reviews in
eviewer
Dr. Jean-Pierre Papazyan, Clinique de Genolier, Nuclearedicine, 1 route du Muids, CH-1272 Genolier, Switzerland.
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iographies
Michael Lin is a Staff Specialist in Nuclear Medicinend PET at the Department of Nuclear Medicine and PET,iverpool Hospital, Sydney, Australia. Conjoint Lecturerf Faculty of Medicine, University of New South Wales,ustralia. Member of the South Western Sydney Colorec-
al Tumour Group, Sydney South West Area Health Service,ydney, Australia. Regional International Adviser and Fellowf the Royal College of Physicians of London and Fellow ofhe Royal Australasian College of Physicians.
Karen Wong is a Staff Specialist in Radiation Oncologyt Liverpool Hospital, Sydney, Australia. Clinical Researchellow at Collaboration for Cancer Outcomes Research andvaluation (CCORE), Liverpool Hospital; Member of theouth Western Sydney Colorectal Tumour Group, Sydneyouth West Area Health Service, Sydney, Australia. Conjointecturer of Faculty of Medicine, University of New Southales, Australia.
Weng Leong Ng is a Staff Specialist in Medical Oncologyt Liverpool Hospital, Sydney, Australia. Clinical Researchellow at Collaboration for Cancer Outcomes Research andvaluation (CCORE), Liverpool Hospital; Member of theouth Western Sydney Colorectal Tumour Group, Sydneyouth West Area Health Service, Sydney, Australia. Conjointecturer of Faculty of Medicine, University of New Southales, Australia.
Ivan Ho Shon is a Senior Staff Specialist in Nuclearedicine and PET at Liverpool Hospital, Sydney, Australia.onjoint Lecturer of Faculty of Medicine, University of Newouth Wales, Australia.
Matthew Morgan is a Visiting Medical Officer, Depart-
ent of Colorectal Surgery, Bankstown Hospital, Sydney,ustralia. Chair of the South Western Sydney Colorectalumour Group, Sydney South West Area Health Service,ydney, Australia.