ReviewEuropean Organisation of Research and Treatment of Cancer (EORTC) Gastrointestinal Group: Workshop on the role of metabolic imaging in the neoadjuvant treatment of gastrointestinal cancer
Introduction
Tumours originating from the gastrointestinal tract organs are amongst the most prevalent cancers worldwide with a particularly high incidence rate of colorectal cancer in the West and of stomach cancer in Asia. The incidence of oesophageal adenocarcinoma is dramatically increasing in countries with a western life style.
After recent studies, multimodal and especially neoadjuvant treatment strategies are now widely used. This is particularly true for localised oesophago-gastric cancers,1, 2, 3 for liver metastases from colorectal cancer4, 5 and for locally advanced rectal cancer.6, 7 Soon after having implemented neoadjuvant treatment in clinical trials and into clinical routine, it became clear that some key issues in the context of neoadjuvant treatment are not yet understood and some relevant clinical problems are not yet solved.
First and foremost, the inaccuracy of clinical staging remains and becomes an even more relevant problem in the times of neoadjuvant treatment. This is because the selection of a patient for neoadjuvant treatment can only be based on clinical evaluation and not longer on histopathological staging. Therefore, it is now crucial to achieve a correct depiction of the TNM status and of other relevant prognostic and predictive factors. Novel imaging techniques such as positron emission tomography (PET) may help to achieve an accurate staging.
Second, in a variety of pre-operatively treated gastrointestinal tumours the response to neoadjuvant treatment appears determinant for the prognosis of patients who then undergo resection.8, 9, 10, 11 Traditionally, response has been determined post-operatively by pathological scoring of tumour regression. But this information comes late, when we aim at tailoring every patient’s treatment according to individual tumour and patient characteristics. Novel imaging techniques may also be useful to determine the chemo-responsiveness of a tumour as early as possible in the course of specific treatment. This would allow altering the treatment by introducing novel or alternative drugs that may overcome chemotherapy resistance or changing the general treatment strategy for the patient.
Third, to accurately quantify the therapeutic response to pre-operative chemo- or radiotherapy is a key issue. Recent studies have shown that conventional pre-operative staging procedures cannot accurately define complete pathological responses.12, 13 However, accurate qualification of complete response is key in deciding on the extent of surgical resections. Sticking to the rule of operating in the limits of the initial tumour extension means that organ or sphincter preservation is often suboptimal even when the patient has achieved a good clinical responses to neoadjuvant treatment. Novel imaging techniques may help to more reliably and precisely define true complete responses to pre-operative treatment, which would allow to limit the radicality of the surgical resection and thus preserve organ function.
The European Organisation of Research and Treatment of Cancer (EORTC) Gastrointestinal (GI) Tract Cancer Group organised a multidisciplinary 2-day workshop in October 2007 to discuss the value of novel imaging techniques, in particular positron emission tomography/computed tomography (PET/CT) in the treatment of potentially curable GI cancer and to elaborate future clinical study concepts to assess the value of these novel imaging techniques.
Section snippets
The role of PET to characterise prognosis and response in the treatment of cancer (Lecture: Robert Downey, New York, USA)
The majority of patients with surgically treated lung and oesophageal cancer die from progression of micro-metastatic disease that is undetected pre-operatively. It is likely that the greatest benefit of surgery will be in those patients responding to induction chemotherapy. Currently imaging defines prognosis prior to induction therapy and measures response to therapy poorly.
The initial promise of PET imaging was that it would allow non-invasive determination of whether an indeterminate organ
Nuclear medicine techniques for early prediction of response to chemotherapy and chemo-radiation in GI cancer (Lecture: Bernd Joachim Krause, Munich, Germany)
Therapy response assessment – especially in the neoadjuvant setting – is a major goal in oncology with an emphasis on assessments taking place early in the course of disease that carry potentially important implications for the therapeutic management of patients.
Amongst surrogate markers allowing therapeutic response assessment 18F-fluordeoxyglucose (FDG) uptake has been identified as a promising marker of response to treatment. The decrease of glucose utilisation during therapy correlates with
Current and new technological approaches when using PET-CT (Lecture: Hartwig Newiger, Erlangen, Germany)
The combination with CT-scans and other new technological advances enhance the precision of positron emission tomography (PET) images. Multi centre trials require precise and quantitative PET data sets.
Important parameters to the standardisation of quantitative PET are, e.g. sensitivity, correction methods and reconstruction algorithms. It is assumed that the system is perfectly normalised and cross-calibrated to a dose calibrator.
Sensitivity of PET systems has recently been improved by the use
What can be the impact of response-guided pre-operative treatment on upper GI surgery? (Lecture: Katja Ott, Heidelberg, Germany)
Neoadjuvant chemo- or radiochemotherapy in locally advanced gastric (GC) – or distal oesophageal adenocarcinoma (AEG-type I) is now accepted as a standard of care. It is a fact, that patients who respond to induction therapy have a significantly improved prognosis compared to patients with non-responding tumours. No pre-therapeutically available molecular markers predicting response and/or prognosis are available so far.
In AEG-type I, FDG-PET was prospectively established as surrogate
How can response to neoadjuvant treatment be assessed on the histopathological level? (Lecture Daniela E. Aust, Dresden, Germany)
It is now accepted that histopathological response to neoadjuvant treatment is a surrogate marker for treatment efficacy, which may predict local recurrence, overall- and disease-free survival and thus may help identify patients at high risk of recurrence or in need for more aggressive adjuvant treatment.
The parameters that can be assessed by post-operative histopathological examination are
- (1)
Downstaging: Reduction of tumour stage by at least one UICC-stage. Example: cT3,cN1,cM0 → ypT3,ypN0,ypM0
The emerging consensus on adjuvant therapy for oesophageal and gastric cancer. US perspective (Lecture: David Ilson, New York, USA)
There are sufficient data now from phase III trials to indicate that surgery alone is inadequate therapy for either oesophageal or gastric cancer.
Pre-operative treatment with cisplatin/5-FU-based chemotherapy improves survival in adenocarcinoma of the oesophagus and stomach, based on data from the recent MAGIC and FFCD trials, although the most convincing data support such therapy in gastric cancer.2, 30
Adding radiotherapy to pre-operative chemotherapy in oesophageal adenocarcinoma achieves
What can be the next steps in the pre-operative treatment of oesophageal and gastric cancer? European perspective (Lecture: Eric Van Cutsem, Leuven, Belgium)
Despite progress in refining the indications for surgery and the improved outcome after primary surgery, a majority of patients with oesophageal and gastric cancer still die from metastases or from locoregional relapse. This has resulted in the exploration of combined therapeutic modalities. Over the last decade, the use of neoadjuvant (induction) protocols aiming at downsizing or downstaging oesophageal cancer and trying to improve the survival has been widely tested. Different trials
Reliability of imaging in the assessment of response to pre-operative chemotherapy in colorectal liver metastases (Lecture: Mostafa El Hajjam, Boulogne – Billancourt, France)
This update aims to determine the accuracy of imaging in the assessment of response to pre-operative chemotherapy.
Multi-detector CT is routinely used to monitor response to chemotherapy according to RECIST criteria. Volumetry of the metastasis may provide a more reliable assessment. Complete radiological response, considered as a good indicator of treatment efficacy, is not correlated to complete pathological response and does not represent cure. Persistent macroscopic or microscopic residual
Is there a way to assess complete response? The pathologist’s perspective (Lecture Catherine Julié, Boulogne, France)
The pathological examination is supposed to be the gold standard for assessing tumour response. But even if the pathological features of response are now well described, this examination has also some limitations.
The pathological features of tumour response consist in the numeric decrease or disappearance of the tumour cells and an increase in fibrosis. The grading systems for tumour regression are based on the amount of tumour cells relative to the amount of fibrosis. Amongst them, the tumour
How to integrate PET-guided treatment algorithms into future studies in GI cancer (Chairs: Florian Lordick, Heidelberg, Germany and Theo Ruers, Amsterdam, Netherlands)
Several potentially interesting study scenarios were designed and discussed in two separate working groups, the other group focussing on oesophageal cancer and the other group focussing on colorectal cancer (Fig. 2, Fig. 3, Fig. 4).
Fig. 2 delineates a study design that randomises patients into one group that receives standard therapy without response monitoring by PET/CT and into one group that receives therapy with response monitoring by PET/CT. In the group with PET/CT-based response
Working group A: Oesophageal cancer (Chairs: Florian Lordick, Heidelberg, Germany; Wolfgang A. Weber, Freiburg, Germany; Arnaud Roth, Geneva, Switzerland)
Ninety percent of oesophageal cancers are characterised by a high tumoural 18F-FDG uptake. They are therefore good target tumours for PET/CT studies. Extensive work has been done in the past to study the value of PET in monitoring early metabolic response to pre-operative chemotherapy in adenocarcinoma of the oesophagus (see lectures of Robert Downey and Katja Ott). The most convincing results of these trials were
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The lack of early metabolic changes measured by PET does negatively impact on
Conclusions
Based on the discussion outlined above, several study designs were drafted and biometrically calculated. These designs were presented to the EORTC GI group at the autumn meeting in Mainz (9–11 November 2008). First, there was a consensus that the feasibility of the study in terms of patient numbers needed to randomise should be given high priority. Second, the majority of group members favoured designs with a greater emphasis on potential improvements of the treatment outcomes over those
Working group B: colorectal cancer (Chairs: Theo Ruers, Amsterdam, Netherlands; Manfred P. Lutz, Saarbrücken, Germany; Patrick Flamen, Brussels, Belgium)
The most interesting situations for PET-based response evaluation are those of potentially resectable liver metastases and of locally advanced rectal cancer. In both situations informations from PET may alter the treatment strategy in terms of the duration of neoadjuvant treatment, the selection of drugs, the dose of radiotherapy (rectal cancer), the choice of the surgical procedure and the indication for adjuvant treatment.
Of note, the optimal PET protocol still needs to be defined, including
Further steps
Based on these discussions trials including metabolic imaging with PET/CT will be proposed for locally advanced oesophageal cancer, for locally advanced rectal cancer and for potentially respectable liver metastases from colorectal cancer. These will be discussed during the further meetings of the EORTC GI group later this year.
References (49)
- et al.
Survival benefi ts from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis
Lancet Oncol
(2007) - et al.
Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates
Ann Oncol
(2005) - et al.
EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und – tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francophone de Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a:a randomised controlled trial
Lancet
(2008) - et al.
Results of the American College of Surgeons Oncology Group Z0050 trial: The utility of positron emission tomography in staging potentially operable non-small cell lung cancer
J Thorac Cardiovasc Surg
(2003) - et al.
PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial
The Lancet Oncology
(2007) - et al.
Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery
Ann Oncol
(2007) - et al.
A meta analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer
Am J Surg
(2003) - et al.
Expert opinion on management of gastric and gastro-oesophageal junction adenocarcinoma on behalf of the European Organisation for Research and Treatment of Cancer (EORTC)-gastrointestinal cancer group
Eur J Cancer
(2008) - et al.
The role and limitations of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan and computerized tomography (CT) in restaging patients with hepatic colorectal metastases following neoadjuvant chemotherapy: comparison with operative and pathological findings
J Gastrointest Surg
(2007) - Medical Research Council Oesophageal Cancer Working Party, Surgical resection with or without preoperative chemotherapy...
Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer
New Engl J Med
Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer
New Engl J Med
Preoperative versus postoperative chemoradiotherapy for rectal cancer
New Engl J Med
Radiation Therapy Oncology Group; USA Intergroup. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by Surgery compared with surgery alone for esophageal cancer
J Clin Oncol
Proposed revision of the esophageal cancer staging system to accommodate pathologic response following preoperative chemoradiation (CRT)
Ann Surg
Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival
Ann Surg
Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer
J Clin Oncol
Complete response of colorectal liver metastases after chemotherapy: Does it mean cure?
J Clin Oncol
Use of oesophagogastroscopy to assess the response of oesophageal carcinoma to neoadjuvant therapy
Br J Surg
The utility of positron emission tomography in staging of potentially operable carcinoma of the thoracic esophagus: Results of the American College of Surgeons Oncology Group Z0060 trial
J Thorac Cardiovasc Surg
Fluorine-18 fluorodeoxyglucose positron emission tomographic maximal standardised uptake value predicts survival independent of clinical but not pathologic TNM staging of resected non-small cell lung cancer
J Thorac Cardiovasc Surg.
Reproducibility of metabolic measurements in malignant tumors using FDG PET
J Nucl Med.
Comparison of different SUV-based methods for monitoring cytotoxic therapy with FDG PET
Eur J Nucl Med Mol Imaging
Standardised uptake values from PET/CT images: comparison with conventional attenuation-corrected PET
Eur J Nucl Med Mol Imaging
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