Elsevier

The Lancet Oncology

Volume 8, Issue 9, September 2007, Pages 797-805
The Lancet Oncology

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PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial

https://doi.org/10.1016/S1470-2045(07)70244-9Get rights and content

Summary

Background

In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET ([18F]FDG-PET) during neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis.

Methods

Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11.

Findings

110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39–59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2·3 years (IQR 1·7–3·0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25·8 months (19·4–32·2) in non-responders (HR 2·13 [1·14–3·99, p=0·015). Median event-free survival was 29·7 months (95% CI 23·6–35·7) in metabolic responders and 14·1 months (7·5–20·6) in non-responders (hazard ratio [HR] 2·18 [1·32–3·62], p=0·002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% [95% CI 48–67]), but no histological response was noted in metabolic non-responders.

Interpretation

This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.

Introduction

After the publication of two randomised controlled trials,1, 2, 3 neoadjuvant chemotherapy has become an accepted choice for the treatment of locally advanced adenocarcinoma of the oesophagus and the oesophagogastric junction. However, for patients who do not respond, the prognosis after neoadjuvant chemotherapy might be worse than that of a primarily surgical approach.4 Additionally, inefficient neoadjuvant treatment leads to adverse events, allows tumour progression during chemotherapy, costs time, and increases health expenses. Therefore, the ability to predict response to chemotherapy is clearly desirable.

Measurement of early changes in tumour glucose uptake by use of 18-fluorodeoxyglucose-PET ([18F]FDG-PET) has yielded reproducible results that are useful for predicting clinical and histopathological response after multiple-course neoadjuvant chemotherapy.5, 6 Specifically, we have noted that when a quantitative threshold for metabolic response is used, PET identifies accurately non-responding tumours within 2 weeks of treatment initiation. This finding suggests that PET can be used to tailor treatment to individual patients.

Studies that show the use of PET results for modifying treatment are currently absent, despite the promising findings of studies evaluating PET for monitoring tumour response during treatment.7 By contrast to previous studies from our institution that assessed and validated the optimum cut-off values for the early prediction of response,5, 6 the study presented here (the Metabolic response evalUatioN for Individualisation of neoadjuvant Chemotherapy in oesOphageal and oesophagogastric adeNocarcinoma (MUNICON) trial prospectively evaluated the feasibility and potential effect on prognosis of administering PET-response-guided chemotherapy to patients with locally advanced adenocarcinoma of the oesophagus and the oesophagogastric junction.

Section snippets

Patients

Patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG) type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) according to Siewert's classification8) were eligible. Patients were staged as cT3 or cT4 based on CT and endoscopic ultrasonography. Haematogenous metastases were excluded by PET. Exclusion criteria were: medical contraindications against chemotherapy with platinum plus fluorouracil; or unacceptable risks for oesophagectomy,

Results

Between May 27, 2002, and Aug 4, 2005, 119 consecutive patients (eight women and 111 men) were enrolled in the study. Eight of these patients were excluded because they did not meet the inclusion criteria—protocol violations were identified by one of the leading investigators (FL, KO, or JRS) within 1 week and led to exclusion from further study treatment and analysis: three patients did not have AEG type 1 or 2, but had subcardiac gastric cancer; two had haematogenous metastases; two had an

Discussion

Our study confirms that early metabolic response measured by PET identifies patients with locally advanced adenocarcinomas of the distal oesophagus and gastric cardia (AEG type 1 and AEG type 2) who have a high chance of achieving major histological responses after neoadjuvant chemotherapy, and therefore, have a favourable prognosis. The study also shows the feasibility of a PET-response-guided treatment algorithm in the management of such tumours.

Individualised, response-guided treatment

References (43)

  • WA Weber et al.

    Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging

    J Clin Oncol

    (2001)
  • K Ott et al.

    Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction

    J Clin Oncol

    (2006)
  • ME Juweid et al.

    Positron-emission-tomography and assessment of cancer therapy

    N Engl J Med

    (2006)
  • JR Siewert et al.

    Classification of adenocarcinoma of the oesophagogastric junction

    Br J Surg

    (1998)
  • H Bartels et al.

    Preoperative risk analysis and postoperative mortality of oesophagectomy for resectable oesophageal cancer

    Br J Surg

    (1998)
  • K Becker et al.

    Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy

    Cancer

    (2003)
  • P Lauren

    The two histological main types of gastric carcinoma: diffuse and so-called intestinal type carcinoma: an attempt at a histo-clinical classification

    Acta Pathol Microbiol Scand

    (1965)
  • BL Brucher et al.

    Neoadjuvant therapy of esophageal squamous cell carcinoma: response evaluation by positron emission tomography

    Ann Surg

    (2001)
  • RJ Downey et al.

    Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: results of a prospective trial

    J Clin Oncol

    (2003)
  • HA Wieder et al.

    Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment

    J Clin Oncol

    (2004)
  • EA Levine et al.

    Predictive value of 18-fluoro-deoxy-glucose-positron emission tomography (18F-FDG-PET) in the identification of responders to chemoradiation therapy for the treatment of locally advanced esophageal cancer

    Ann Surg

    (2006)
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