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Eur J Cardiothorac Surg 2008;33:1112-1116. doi:10.1016/j.ejcts.2008.01.055
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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The decision to operate: role of integrated computed tomography positron emission tomography in staging oesophageal and oesophagogastric junction cancer by the multidisciplinary team

Richard G. Berrisforda,*, Wei-Lup Wongb, David Daya, Elizabeth Toya, Mark Napiera, Keith Mitchella, Saj Wajeda

a Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, United Kingdom
b Paul Strickland Scanner Centre, Northwood, United Kingdom

Received 26 June 2007; received in revised form 20 December 2007; accepted 16 January 2008.

* Corresponding author. Tel.: +44 1392 402689; fax: +44 1302 402175. (Email: richard.berrisford{at}rdeft.nhs.uk).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Our objective was to assess the role of fusion positron emission tomography-computed tomography (PET-CT) in staging patients for minimally invasive oesophagectomy (MIO) with potentially resectable disease from the perspective of a multidisciplinary team (MDT) deciding on operability with conventional staging investigations. Methods: Fifty consecutive patients presenting with potentially operable oesophageal or oesophagogastric junctional tumours were staged with computed tomography (CT) and endoluminal ultrasound (EUS). The MDT categorised patients as group A (n = 33; CT N0M0) or group B (n = 17; CT N1/possible M1). All patients underwent FDG PET-CT. Patients with localised disease (at T3), including single level N1 disease on PET-CT, were deemed suitable for induction chemotherapy followed by surgery. Results: PET-CT re-categorised 12% of patients as inoperable on grounds of distant metastases (four in group A, two in group B). Five patients did not proceed to resection for other reasons. Two had metastatic disease at thoracoscopy. Resection specimens (n = 37) contained 24 nodes (median). Compared with pN status, positive predictive value of PET-CT was 40% and negative predictive value was 43%. The expected PET-CT N1 group had the highest mean number of involved nodes. Median survival for all patients (n = 50) was 31.9 months for group A compared with 17.3 months for group B (not statistically significant). There was no significant difference between patients who were PET-CT N0 or N1 in survival or disease-free survival in patients undergoing surgery (n = 37). Conclusions: PET-CT informs the MDT decision to operate in avoiding futile surgery in stage IV disease or widespread nodal disease. In this study, overall PET-CT N1 status has low positive and negative predictive value for overall pN status.

Key Words: Lymph nodes • Oesophageal neoplasm • Oesophagogastric junction neoplasm • Neoplasm staging • Prospective studies • Positron emission tomography


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Accurate staging of oesophageal cancer is of paramount importance to patient selection. Oesophagectomy has a long-lasting deleterious effect on patients’ quality of life which is unlikely to return to preoperative levels for 6–9 months after open surgery [1]. Survival after resection of oesophageal cancer is poor, with a median survival as low as 13.3 months [2].

It is well known that FDG PET is a useful adjunct to CT in detecting occult metastatic disease or otherwise unknown primary cancers, with an incidence of around 20% for patients with disease assessed as locoregional by CT [3]. FDG PET is less useful for staging local disease, with a specificity of 84% and a lower sensitivity (51%) [3]. The advantage in this scenario, though, is in identifying metastases in lymph nodes that are not pathologically enlarged, especially first tier regional lymph nodes (left gastric artery).

The advent of fusion FDG PET-CT has given added value to PET images as their fusion with CT images allows much more precise interpretation, with CT derived anatomy being functionally labelled by PET data. Patients can avoid futile surgery after fusion PET-CT mainly because of detection of occult distant metastases [4]. Little has been published on the additional role of fusion FDG PET-CT in determining the appropriateness of surgery in patients with bulky disease on conventional CT and EUS staging.

The aim of this study is to assess the additional role of fusion PET-CT in staging patients for minimally invasive oesophagectomy (MIO) with potentially resectable disease from the perspective of a multidisciplinary team deciding on operability using CT and EUS.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Fifty consecutive patients with potentially operable, biopsy-proven carcinoma of the oesophagus or gastro-oesophageal junction were sent for FDG PET-CT scanning to a tertiary imaging centre as part of their preoperative staging protocol. These patients had been reviewed at the multidisciplinary team meeting; their pretreatment CT scan was examined.

They were categorised into two groups according to UICC 2002 TNM appropriate for the site of the tumour. Group A was assessed as N0M0 on CT. Group B was assessed as N1 and/or borderline M1 on CT.

On reviewing the PET-CT, patients were considered inoperable where the PET-CT confirmed distant metastatic disease or where there was high activity in multiple lymph node sites, distant to the regional group of lymph nodes. Patients whose PET-CT positive regional nodes were confined to the left gastric artery group went on to have neoadjuvant chemotherapy followed by MIO. A few patients with bulky (>2 cm) but localised left gastric artery disease underwent staging laparoscopy prior to neoadjuvant chemotherapy.

Patients with tumours staged T3 and/or N1 underwent neoadjuvant chemotherapy with 1–3 cycles of platinum based chemotherapy [2,5] (Platinum – 5FU or Epirubicin-Platinum-5FU), followed by repeat CT scan to look for disease progression. Resection was undertaken with a totally minimally invasive technique [6,7], namely thoracoscopic oesophageal mobilisation, laparoscopic gastric conduit formation and cervical anastomosis. Radical two-field lymphadenectomy was undertaken routinely. The resected specimen was dissected in theatre, with the surgeon removing standard nodal stations from the fresh specimen. Outcome was assessed by retrospective analysis of prospectively collected data. Patients who completed resection were divided into four groups for analysis, based on PET-CT regional lymph node status:

• Expected PET-CT Regional N0 (CT Regional N0).
• Unexpected PET-CT Regional N0 (CT Regional N1).
• Expected PET-CT Regional N1 (CT Regional N1).
• Unexpected PET-CT Regional N1 (CT Regional N0).

Pathological overall nodal status, pathological regional nodal status and outcome were analysed for these four groups.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The study population comprised 50 patients (44 male, 6 female) with a mean age of 66.4 years (range 44–81) who presented with oesophageal or oesophagogastric junction tumours (patients with predominantly gastric tumours, including Siewert type III were not included). Tumours were located at the oesophagogastric junction (n = 28), lower third (n = 16), and middle third (n = 6). Histology was adenocarcinoma (n = 45), squamous (n = 4), small cell (n = 1). Follow-up was available for all but one patient. The patient with small cell histology became unfit for resection during diagnostic workup.

All patients underwent CT and subsequent PET-CT prior to starting chemotherapy. Thirty-two patients underwent EUS (18 had been referred from other units without EUS prior to chemotherapy). For this reason we have not included EUS nodal findings in the analysis. No patient undergoing EUS was found to have a T4 lesion.

3.1 Decision to operate prior to PET-CT
On CT and EUS criteria, before the patient underwent PET-CT, the multidisciplinary team decided that 17 patients (17/50, 34%) were clearly operable (group A) and 33 patients (33/50, 66%) had some reservation to operation (group B) (Table 1 ).


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  		Table 1 Effect of PET-CT on the decision to operate
 
3.2 Decision to operate after PET-CT
3.2.1 Unexpected M1 disease on PET-CT (M0 on CT)
Across both groups, six patients (6/50, 12%) were unexpectedly found to be inoperable, four from group A, two from group B. In group A, PET-CT uncovered multifocal distant metastases (n = 2) or nodal activity outside regional nodes (n = 2) (one of these patients also had a 3 mm liver metastasis on staging laparoscopy). In group B, PET-CT demonstrated widespread metastasis (n = 1), and liver metastases amongst liver cysts (n = 1). In this series, no patient was found to have another unexpected primary.

3.2.2 Operability of patients without distant nodal or other metastatic disease
Of the remaining 44 patients, two progressed on chemotherapy, one became unfit for surgery, one was discovered to have a primary pancreatic ampullary tumour, and one had fixed nodal disease at laparoscopy. Thirty-nine patients were listed for minimally invasive resection, two of whom were found to have unexpected metastases in the pleura or lung during the thoracoscopic phase of MIO (resection was not undertaken). The following analysis was undertaken on the remaining 37 patients who underwent resection over a 24-month period. There was one postoperative death from delayed mediastinal haemorrhage of unknown origin at day 12.

3.2.3 Pathological examination of lymph nodes
Median number of lymph nodes harvested was 24 (interquartile range: 20–28, range: 7–48). Thirteen patients (13/37, 35%) were pN0. Median number of involved nodes (all patients undergoing resection) were 2 (IQR: 0–5, range: 0–16). Data on lymph node histology are summarised in Table 2 .


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  		Table 2 Pathological examination of lymph nodes from resected specimens (n = 37)
 
3.2.4 PET-CT nodal predictions compared with pN findings at resection
Pathological lymph node status in resected patients is shown in Table 2 and Fig. 1 .


Figure 1
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  		Fig. 1. Scatter plot of pN findings according to PET-CT category. Mean and SEM bars shown. Extra capsular extension shown as red data points. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

 
There was no significant difference between the four groups as shown in Fig. 2 although the mean number of involved nodes was higher in the expected PET-CT N1 group. Table 3 shows numbers in each group and calculations for specificity, sensitivity, positive predictive value and negative predictive value.


Figure 2
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  		Fig. 2. Overall survival for all patients (n = 50) by MDT category (group A or B) prior to information from PET-CT. Number at risk shown in table. Plot truncated at 24 months.

 

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  		Table 3 Sensitivity analysis of CT PET locoregional nodal status compared with histological examination* of regional nodes (patients undergoing resection, n = 37)
 
3.3 Survival
Median overall survival for all patients (n = 50) by MDT category (group A or B) prior to information from PET-CT was 31.9 months (group A) compared with 17.3 months (group B, not significant, Fig. 2). Median overall survival of patients undergoing resection (n = 37) by PET-CT Regional N Status was 31.9 months for PET-CT N0 and 35.7 months for PET-CT N1 (not significant, Fig. 3 ). Median disease-free survival calculated from all follow-up available in operated patients was 25.8 months for PET-CT N0 compared with 27.1 months for PET-CT N1 (not significant, shown truncated at 24 months in Fig. 4 ). Nine of the 10 patients in the resected group had distant recurrence, one had local recurrence.


Figure 3
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  		Fig. 3. Overall survival of patients undergoing resection (n = 37) by PET-CT Regional N Status Number at risk shown in table. Plot truncated at 24 months.

 

Figure 4
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  		Fig. 4. Disease-free survival of patients undergoing resection (n = 37) by PET-CT Regional N Status Number at risk shown in table. Plot truncated at 24 months.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The most relevant finding in this study is that 6/50 (12%) of patients have avoided futile surgery for stage IV disease which was not apparent on conventional staging. This confirms the findings of several other authors, that in the era of PET (not PET-CT), this additional modality identified significant numbers of patients with unexpected distant nodal or organ metastases [8–13]. Detection rates varied in these series up to 20% [13]. PET (not PET-CT) has been found to have a sensitivity of 81% and a specificity of 91% in detecting distant metastases [14]

Four patients from group A and two from group B on conventional staging were found to have unexpected distant metastases on PET-CT. This is relevant to the decision to undertake PET-CT in areas where access to such imaging is difficult. It appears that all potentially operable patients by conventional staging warrant PET-CT, even in the absence of bulky disease or enlarged locoregional nodes.

A further 2/50 (4%) patients in this series also avoided futile open surgery through the discovery of unexpected metastatic disease at the first (thoracoscopic) stage of MIO.

CT alone, although accurate in demonstrating nodes which are potentially pathological on size criteria, has a sensitivity of 84% and specificity of 67% for identifying involved N1 nodes [14]. The addition of FDG PET to images may not significantly improve accuracy in identifying pN1 nodes which are local to the tumour because of high uptake in the adjacent tumour tissue [15]. Sensitivity of PET alone to detect local nodal disease has been reported to be anything from 22% to 82% [14,16–18]. A meta-analysis of studies assessing the value of FDG PET in nodal staging has estimated a pooled sensitivity of 51% and specificity of 84% [19].

It is difficult to assess accuracy of locoregional nodal status by comparing with the ‘gold standard’ of pathological examination from the resected specimen. We have performed a radical nodal dissection in these patients to assess true nodal status as far as possible (median harvest 24 (interquartile range 21–18)). However, response to chemotherapy or subtle progression on chemotherapy will lessen the accuracy of assessment of these nodes in the interval between PET-CT and resection. In this study, we found sensitivity of PET-CT for pN1 disease to be 75% but specificity was much lower than the pooled results at 14%. This reflects small numbers in the PET-CT N1 group undergoing surgery. The positive and negative predictive values of 40% and 43% respectively suggest that information from PET-CT regarding nodal status should be interpreted with caution in informing the decision to operate. This is further emphasised by the lack of difference in survival and disease-free survival curves in the first 2 years after resection.

Ott [3] states that ‘the initial staging of regional lymph nodes is less important because at the moment there is no pre-therapeutic therapy stratification based on lymph node category.’ If PET-CT positivity is a surrogate for high numerical lymph node burden, are patients with PET-CT N1 disease less suitable for resection? This is a difficult question to answer, as the benefits for chemotherapy in the OEO2 and MAGIC trials [2,5] were based on clearly operable (group A in this study) rather than borderline patients (group B in this study). In this context, use of PET [20,21] or PET-CT [4] to assess the response to chemotherapy may be indicated.

Survival analysis shows a trend towards longer overall survival in group A compared with group B. This in is accordance with clinical expectations. It is perhaps surprising, then, that there is little difference (at short follow-up) between overall survival in PET-CT N0 and PET-CT N1 patients. However, the trend towards early recurrence is seen in Fig. 4 where the increasing proportion of recurrence leads to a divergence in disease-free survival. The numbers in the PET-CT N1 group are small; the trend to early recurrence in this group needs further study with larger populations. It is uncertain how important it is for this group to show significant response to chemotherapy before being offered surgery, considering that palliative chemotherapy without surgery only leads to a 2–3 month survival advantage over supportive care alone [22]. Prospective studies are needed to look at outcome in prechemotherapy PET-CT N1 patients. We need to know what the role of surgery is in these patients, whether it confers a survival advantage, what the cost is in quality of life, and what role PET-CT has to play in assessing response to neoadjuvant therapy.


   Acknowledgments
 
The authors would like to thank Peter Froeschle and Rakesh Krishnadas for their clinical care of many of these patients, as well as the upper GI MDTs in Exeter and North Devon, UK.


   Footnotes
 
{star} Presented at the 15th European Conference on General Thoracic Surgery, Leuven, Belgium, June 3–6, 2007.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Blazeby JM, Farndon JR, Donovan J, Alderson D. A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer 2000;88:1781-1787.[CrossRef][Medline]
  2. Medical Research Council Working Group on oesophageal cancer. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002;359:1727–33.
  3. Ott K, Weber W, Siewert JR. The importance of PET in the diagnosis and response evaluation of esophageal cancer. Dis Esophagus 2006;19:433-442.[CrossRef][Medline]
  4. Erasmus JJ, Munden RF. The role of integrated computed tomography positron-emission tomography in esophageal cancer: staging and assessment of therapeutic response. Semin Radiat Oncol 2007;17:29-37.[CrossRef][Medline]
  5. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, Magic TP. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20.[Abstract/Free Full Text]
  6. Luketich JD, Schauer PR, Christie NA, Weigel TL, Raja S, Fernando HC, Keenan RJ, Nguyen NT. Minimally invasive esophagectomy. Ann Thorac Surg 2000;70:906-911.[Abstract/Free Full Text]
  7. Luketich JD, velo-Rivera M, Buenaventura PO, Christie NA, McCaughan JS, Litle VR, Schauer PR, Close JM, Fernando HC. Minimally invasive esophagectomy: outcomes in 222 patients. Ann Surg 2003;238:486-494.[Medline]
  8. Flamen P, Lerut A, Van CE, De WW, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, De LP, Van RD, Coosemans W, Ectors N, Haustermans K, Mortelmans L. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18:3202-3210.[Abstract/Free Full Text]
  9. Liberale G, Van Laethem JL, Gay F, Goldman S, Nagy N, Coppens E, Gelin M, El NI. The role of PET scan in the preoperative management of oesophageal cancer. Eur J Surg Oncol 2004;30:942-947.[CrossRef][Medline]
  10. van Westreenen HL, Heeren PA, van Dullemen HM, van der Jagt EJ, Jager PL, Groen H, Plukker JT. Positron emission tomography with F-18-fluorodeoxyglucose in a combined staging strategy of esophageal cancer prevents unnecessary surgical explorations. J Gastrointest Surg 2005;9:54-61.[CrossRef][Medline]
  11. Flanagan FL, Dehdashti F, Siegel BA, Trask DD, Sundaresan SR, Patterson GA, Cooper JD. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography. AJR Am J Roentgenol 1997;168:417-424.[Abstract/Free Full Text]
  12. Luketich JD, Friedman DM, Weigel TL, Meehan MA, Keenan RJ, Townsend DW, Meltzer CC. Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans. Ann Thorac Surg 1999;68:1133-1136.[Abstract/Free Full Text]
  13. Weber WA, Ott K. Imaging of esophageal and gastric cancer. Semin Oncol 2004;31:530-541.[CrossRef][Medline]
  14. Lowe VJ, Booya F, Fletcher JG, Nathan M, Jensen E, Mullan B, Rohren E, Wiersema MJ, Vazquez-Sequeiros E, Murray JA, Allen MS, Levy MJ, Clain JE. Comparison of positron emission tomography, computed tomography, and endoscopic ultrasound in the initial staging of patients with esophageal cancer. Mol Imaging Biol 2005;7:422-430.[CrossRef][Medline]
  15. Rice TW. Clinical staging of esophageal carcinoma. CT, EUS, and PET. Chest Surg Clin N Am 2000;10:471-485.[Medline]
  16. Lerut T, Flamen P, Ectors N, Van CE, Peeters M, Hiele M, De WW, Coosemans W, Decker G, De LP, Deneffe G, Van RD, Mortelmans L. Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esophagus and gastroesophageal junction: A prospective study based on primary surgery with extensive lymphadenectomy. Ann Surg 2000;232:743-752.[Medline]
  17. Kneist W, Schreckenberger M, Bartenstein P, Grunwald F, Oberholzer K, Junginger T. Positron emission tomography for staging esophageal cancer: does it lead to a different therapeutic approach?. World J Surg 2003;27:1105-1112.[CrossRef][Medline]
  18. Heeren PA, Jager PL, Bongaerts F, van DH, Sluiter W, Plukker JT. Detection of distant metastases in esophageal cancer with (18)F-FDG PET. J Nucl Med 2004;45:980-987.[Abstract/Free Full Text]
  19. van Westreenen HL, Westerterp M, Bossuyt PM, Pruim J, Sloof GW, van Lanschot JJ, Groen H, Plukker JT. Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 2004;22:3805-3812.[Abstract/Free Full Text]
  20. Chao KS. Functional imaging for early prediction of response to chemoradiotherapy: 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography – a clinical application model of esophageal cancer. Semin Oncol 2006;33(Suppl 11):59-63.[CrossRef]
  21. Munden RF, Macapinlac HA, Erasmus JJ. Esophageal cancer: the role of integrated CT-PET in initial staging and response assessment after preoperative therapy. J Thorac Imaging 2006;21:137-145.[CrossRef][Medline]
  22. Price T, Waters J, Cunningham D, Norman A, Hill M, Scarffe H, Harper P, Nicolson M, Seymour M, Hickish T, Iveson T, Oates J. Palliative chemotherapy in oesophageal carcinoma: evidence for clinical benefit. Proc Am Soc Clin Oncol 2000:19(abstr 1228).




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