Value of complete metabolic response by 18F-fluorodeoxyglucose-positron emission tomography in oesophageal cancer for prediction of pathologic response and survival after preoperative chemoradiotherapy

doi:10.1016/j.ejca.2007.04.001

European Journal of Cancer

Volume 43, Issue 9, June 2007, Pages 1385-1391

https://doi.org/10.1016/j.ejca.2007.04.001 Get rights and content

Abstract

We aimed to assess the ability of ¹⁸F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan to predict pathologic complete response (CR) and survival in patients with oesophageal cancer treated with preoperative chemoradiotherapy (CRT). The study cohort consisted of 62 consecutive patients with operable oesophageal cancer who were treated with preoperative CRT followed by oesophagectomy. Endoscopy, computed tomography (CT) and PET were performed before and after CRT.

Of the 62 patients, 56 (90%) patients responded to preoperative CRT. FDG-PET-determined complete metabolic response (CMR) was achieved by 33 patients (54.1%), whereas pathologic CR was achieved by 28 patients (45.2%). Compared with endoscopic biopsy or CT scan, CMR by FDG-PET showed the highest correlation with pathologic CR (concordance, 71%). At a median follow-up of 19.3 months (range, 3.9–57.1 months), median overall survival (OS) was not reached in patients with CMR compared to 22.4 months in patients who did not achieve CMR. Median disease free survival (DFS) was not reached in patients with CMR compared to 17.4 months in patients who did not achieve CMR. By multivariate analysis, CMR by FDG-PET was significantly associated with better DFS and OS (P = 0.006, P = 0.033, respectively). The variables associated with pre-CRT PET scan were not predictive of survival.

In conclusion, CMR by FDG-PET has a significant correlation with pathologic CR and can predict the long-term outcome in oesophageal cancer patients undergoing CRT. Although surgery is standard treatment for respectable oesophageal cancer, currently even in patients with CMR, the addition of ¹⁸F-FDG-PET could be used to select the patient subgroup not requiring surgery.

Introduction

Despite conflicting results from randomised trials, concurrent chemoradiotherapy (CRT) followed by oesophagectomy has become the standard treatment option, with about 70% of patients receiving preoperative CRT undergoing esophagectomy.1, 2, 3, 4 Of resected patients, 11–56% achieve pathologic complete response (CR), and patients who achieve pathologic CR survive longer than those who do not.5, 6, 7 In spite of improvements in surgical techniques, however, the postoperative mortality rate from oesophagectomy has been reported to be about 5–9%.⁸ Furthermore, a recent European trial found no overall survival (OS) benefit when oesophagectomy was added to CRT, particularly for patients who responded to chemoradiotherapy.⁹ This finding, in combination with the postoperative mortality rate from oesophagectomy, suggests that surgery may be detrimental for patients who have achieved pathologic CR after preoperative CRT. In addition, the increased rate of pathologic CR after preoperative CRT indicates a need for a surrogate marker that can predict pathologic CR in response to preoperative therapy.

Conventional structure-based imaging techniques, such as computed tomography (CT), endoscopy and endoscopic ultrasonography (EUS), are generally considered inaccurate in predicting response to CRT, primarily because these modalities cannot differentiate between viable tumours and inflammatory reactions, oedema, and fibrosis.10, 11 [¹⁸F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET), however, is a functional imaging modality that can detect changes in tissue metabolism that usually precede structural imaging response.12, 13 Current evidence suggests that ¹⁸F-FDG PET can identify patients who achieve a pathologic response to neoadjuvant treatment prior to surgical resection, as well as being able to predict long-term survival.14, 15, 16 We previously showed that the pathologic response of initially highly metabolic tumour after preoperative CRT could correlate with the metabolic response.¹⁷ However, it is not clear whether complete metabolic response (CMR), as assessed by FDG-PET, reflects pathologic CR.

We therefore evaluated the accuracy of CMR assessed by FDG PET in predicting pathologic CR in patients with operable oesophageal cancer who underwent neoadjuvant CRT, as well as the ability of ¹⁸F-FDG PET to predict long-term survival after preoperative CRT followed by surgery.

Section snippets

Eligibility

Beginning in March 1999, we have performed prospective phase II and phase III clinical trials in locally advanced but resectable oesophageal cancer.4, 6 FDG-PET was introduced as a diagnostic tool in March 2001, and patients were evaluated with FDG-PET before and after CRT. Of the 89 consecutive patients who underwent FDG PET before and after CRT, 27 did not undergo oesophagectomy due to patient refusal, disease progression or poor general condition. Because the aim of this study was to

Patient characteristics

The characteristics of the 62 patients are summarised in Table 1. Histologically, all primary tumours were squamous cell carcinomas.

Tumour response post-CRT

All patients underwent pre- and post-CRT endoscopy, oesophagography, CT scan and FDG-PET scan. The median time interval between the end of preoperative CRT and post-CRT PET scan was 25 days (range, 15–59 days). Fusion PET/CT imaging was performed in 27 patients (43.5%). Clinically, 56 patients (90.3%) were considered as responders after preoperative CRT. After the

Discussion

Up to 40% of these patients have been reported to achieve pathologic CR after preoperative CRT, with the proportion being higher in patients with squamous cell carcinoma than in those with adenocarcinoma. In addition, the authors had experienced in previous studies that about 50% of patients who received preoperative CRT achieved pathologic CR.4, 6 Considering the morbidity of oesophagectomy and adverse effects for quality of life, if it is possible to predict whether patients will achieve

Conflict of interest statement

None declared.

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Cited by (113)

Can Clinical Response Predict Pathologic Response Following Neoadjuvant Chemoradiation for Esophageal Cancer?
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Approximately 20–40% of patients with locally advanced esophageal cancer will achieve a pathologic complete response (ypCR) following neoadjuvant chemoradiotherapy (nCRT). Predicting ypCR based on a clinical complete response (ycCR) has been a challenge. This study assessed the correlation between ycCR and ypCR, as determined from esophagectomy specimens.
Patients undergoing esophagectomy following nCRT at three major institutions between 2005 and 2018 were reviewed. Restaging, including PET/CT, endoscopy with biopsy, and esophageal ultrasound (EUS), was performed to determine ycCR.
Six hundred sixty patients were included, with 93.3% with esophageal adenocarcinoma histology. Six hundred fifty-eight of these patients underwent PET, 304 EUS, and 584 underwent a biopsy. Following nCRT, 148 (22.4%) were found to have a ypCR. Only 12/32 (37.5%) determined to have a ycCR were found to have a ypCR, while 136/628 (21.6%) with a non-ycCR were found to have a ypCR (p 0.075). Individual modality PPV was 28% for PET, 54% for EUS, and 26% for biopsy. When PET was combined with EUS, 168 reports were concordant and the PPV of ypCR was 50%, though the number of patients was low (1/2). With all 3 re-staging modalities combined, the PPV and NPV both rose to 100%.
Current restaging tools cannot reliably predict ypCR after nCRT. While multimodal restaging appears to be a more accurate predictor of ypCR than any testing modality alone, patients cannot reliably be advised to avoid an esophagectomy on the assumption that ycCR predicts ypCR at this time.
Detecting Pathological Complete Response in Esophageal Cancer after Neoadjuvant Therapy Based on Imaging Techniques: A Diagnostic Systematic Review and Meta-Analysis
2019, Journal of Thoracic Oncology
Citation Excerpt :
In total, 57 studies involving 3660 patients met the inclusion criteria. An overview of the study characteristics are provided in Table 1.22–77 The following imaging techniques were used to diagnose ypCR: CT (eight studies),22–29 PET(-CT) (35 studies),14,23,25,30–61 EUS (15 studies),28,60,62–74 and MRI (three studies).75–77
Up to 32% of patients with esophageal cancer show a pathological complete response (ypCR) after neoadjuvant therapy. To prevent overtreatment, the indication to perform esophagectomy in these patients should be reconsidered. Implementing an organ-preserving strategy for patients with ypCR requires an accurate assessment of residual disease after neoadjuvant treatment. The aim of this study was to systematically review the effectiveness of imaging techniques used for detection of ypCR after neoadjuvant therapy but before resection in patients with esophageal cancer.
A systematic literature search of the Medline, Embase, and Cochrane Library databases was performed from January 1, 2000, to December 13, 2017. Eligible studies were diagnostic studies that compared results of imaging modalities after neoadjuvant therapy to histopathological findings in the resection specimen after esophagectomy. Methodological quality was assessed by the Cochrane Quality Assessment of Diagnostic Accuracy Studies, version 2, model. Primary outcome measures were true positive, false-positive, false-negative, and true negative values of imaging techniques predicting ypCR. A meta-analysis was performed by pooling sensitivities and specificities by using a bivariate model.
A total of 4420 articles were identified. After exclusion of irrelevant titles and abstracts, 360 articles were reviewed in full text. In total, four imaging modalities (computed tomography [CT], positron emission tomography [PET-CT], endoscopic ultrasound [EUS], and magnetic resonance imaging [MRI]) were used for restaging. The meta-analysis was conducted with data from 56 studies involving 3625 patients. The pooled sensitivities of CT, PET-CT, EUS, and MRI for detecting ypCR were 0.35, 0.62, 0.01 and 0.80, respectively, whereas the pooled specificities were 0.83, 0.73, 0.99, and 0.83, respectively. The positive predictive value in detecting ypCR was 0.47 for CT, 0.41 for PET-CT, not applicable for EUS, and 0.61 for MRI.
Current imaging modalities such as CT, PET-CT, and EUS seem to be insufficiently accurate to identify complete responders. More accurate diagnostic tests are needed to improve restaging accuracy for patients with esophageal cancer.
Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study
2018, The Lancet Oncology
After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations.
The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin [area under the curve 2 mg/mL per min] plus paclitaxel [50 mg/m² of body-surface area] combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4–6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET–CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12–14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed.
Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% [95% CI 17–50]) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% [95% CI 4–23]) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% [95% CI 17–44]). PET–CT missed six of 41 TRG3 or TRG4 tumours (15% [95% CI 7–28]). PET–CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas).
After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET–CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803).
Dutch Cancer Society.
Esophageal cancer
2019, Medecine Nucleaire
Neoadjuvant chemoradiotherapy for resectable oesophageal cancer
2018, Best Practice and Research: Clinical Gastroenterology
Citation Excerpt :
CT has only a moderate accuracy for detecting residual disease after nCRT [44]. According to three prospective studies, endoscopic biopsy demonstrated a sensitivity and specificity of 30–40% and 100%, respectively [45–47]. Response evaluation by EUS showed a sensitivity of 95–100% and a specificity of 0–47% in three prospective studies [47–49].
At present, treatment of potentially curable oesophageal cancer includes neoadjuvant chemoradiotherapy followed by oesophagectomy. Alternatively, neoadjuvant chemotherapy is used. To date, strong evidence on the superiority of one modality over the other has not been provided. Currently, up to one-third of patients show a pathologically complete response after neoadjuvant chemoradiotherapy. To optimise the efficacy of neoadjuvant treatment for individual patients, prediction of response to neoadjuvant treatment is highly desired. Therefore, several clinical diagnostic modalities have been investigated for early response evaluation, of which positron emission tomography (PET) has been studied most extensively. To identify patients who might benefit from postponing or even omitting surgery, recent advances have been made in evaluating response after completion of neoadjuvant chemoradiotherapy. This review provides an overview of current evidence and recent advances in neoadjuvant chemoradiotherapy for oesophageal cancer and discusses the use of neoadjuvant chemotherapy compared to chemoradiotherapy. Moreover, clinical response evaluation to neoadjuvant chemoradiotherapy is reviewed.
Remarkable response as a new indicator for endoscopic evaluation of local efficacy of non-surgical treatments for esophageal cancer
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Value of complete metabolic response by 18F-fluorodeoxyglucose-positron emission tomography in oesophageal cancer for prediction of pathologic response and survival after preoperative chemoradiotherapy

Abstract

Introduction

Section snippets

Eligibility

Patient characteristics

Tumour response post-CRT

Discussion

Conflict of interest statement

Ann Oncol

Ann Thorac Surg

Ann Oncol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Ann Thorac Surg

Gastrointest Endosc

A comparison of multimodal therapy and surgery for esophageal adenocarcinoma

N Engl J Med

Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus

N Engl J Med

Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma

J Clin Oncol

Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival

J Clin Oncol

A phase II trial of preoperative one cycle of induction chemotherapy[capecitabine(CAP), CDDP] followed by concurrent chemoradiation(CRT) in patients with resectable esophageal cancer

J Clin Oncol

Phase II evaluation of preoperative chemoradiation and postoperative adjuvant chemotherapy for squamous cell and adenocarcinoma of the esophagus

J Clin Oncol

Value of complete metabolic response by ¹⁸F-fluorodeoxyglucose-positron emission tomography in oesophageal cancer for prediction of pathologic response and survival after preoperative chemoradiotherapy