Postchemoradiotherapy Positron Emission Tomography Predicts Pathologic Response and Survival in Patients With Esophageal Cancer

doi:10.1016/j.ijrobp.2011.12.029

International Journal of Radiation OncologyBiologyPhysics

Volume 84, Issue 2, 1 October 2012, Pages 471-477

Presented at the 53rd American Society for Radiation Oncology (ASTRO) Annual Meeting, Miami Beach, FL, October 2–6, 2011.

https://doi.org/10.1016/j.ijrobp.2011.12.029 Get rights and content

Purpose

To correlate the prechemoradiotherapy (CRT) and post-CRT metabolic tumor volume (MTV) on positron emission tomography (PET) scanning with the pathologic response and survival in patients receiving preoperative CRT for esophageal cancer.

Materials and Methods

The medical records of 37 patients with histologically confirmed Stage I–IVA esophageal cancer treated with CRT with or without surgical resection were reviewed. Of the 37 patients, 21 received preoperative CRT (57%) and 16 received definitive CRT (43%). All patients had a pre-CRT and 32 had a post-CRT PET scan. The MTV was measured on the pre-CRT PET and post-CRT PET scan, respectively, using a minimum standardized uptake value (SUV) threshold x, where x = 2, 2.5, 3, or the SUV maximum × 50%. The total glycolytic activity (TGA_x) was defined as the mean SUV × MTV_x. The MTV ratio was defined as the pre-CRT PET MTV/post-CRT MTV. The SUV ratio was defined similarly. A single pathologist scored the pathologic response using a tumor regression grade (TRG) scale.

Results

The median follow-up was 1.5 years (range, 0.4–4.9). No significant correlation was found between any parameters on the pre-CRT PET scan and the TRG or overall survival (OS). Multiple post-CRT MTV values and post-TGA values correlated with the TRG and OS; however, the MTV_2.5Post and TGA_2.5Post had the greatest correlation. The MTV₂ ratio correlated with OS. The maximum SUV on either the pre-CRT and post-CRT PET scans or the maximum SUV ratio did not correlate with the TRG or OS. Patients treated preoperatively had survival similar compared with those treated definitively with a good PET response (p = 0.97) and significantly better than that of patients treated definitively with a poor PET response (p < 0.0001).

Conclusion

The maximum SUV was not a predictive or prognostic parameter. The MTV_2.5 and TGA_2.5 were useful markers for predicting the response and survival on the post-CRT PET scan. The MTV₂ ratio also correlated with survival. Post-CRT PET can potentially guide therapy after CRT.

Introduction

Esophageal cancer is an uncommon but deadly malignancy. In 2010, an estimated 16,640 new cases and 14,500 patients died of this disease (1). The overall prognosis remains poor, with an overall 5-year survival rate of <15%. Although the optimal treatment remains controversial, locally advanced disease is commonly treated with combined modality therapy with chemoradiotherapy (CRT) with or without surgery.

Preoperative CRT followed by surgical resection has been shown to improve survival compared with surgery alone 2, 3. Other studies have suggested that definitive CRT alone, with surgery reserved for salvage, might provide equivalent results compared with a surgical approach 4, 5, 6. Investigators have evaluated the role of positron emission tomography (PET) after chemotherapy and/or radiotherapy (RT) as a predictive and prognostic assay tool 7, 8, 9, 10, 11, 12 to potentially individualize therapy according to the patient’s risk profile, similar to the trial strategy of MUNICON I (13).

These studies have mostly examined the maximum standardized uptake value (SUV_max) to determine the treatment response. More recently, the metabolic tumor volume (MTV) has emerged as an important prognostic indicator in several malignancies, including head-and-neck, lung, and pancreatic cancer 14, 15, 16 and, in some cases, might be a more accurate predictor of the tumor response than the SUV alone (17). Hyun et al. (18) reported that the MTV was a more accurate predictor of survival than the SUV in esophageal cancer patients. The aim of the present study was to compare the predictive and prognostic values of SUV and MTV on the pre- and post-treatment scans of patients with esophageal and gastroesophageal cancer.

Section snippets

Methods and Materials

In the present institutional review board-approved study, 37 patients with histologically confirmed clinical Stage T2-T4 or N+ esophageal cancer treated with CRT with or without surgical resection with curative intent who had a PET/computed tomography (CT) scan as a part of the RT planning process at our institution between February 2005 and January 2011 were included in this study. No patients had received any previous therapy. Staging was determined with CT with or without PET (n = 17) or

Results

The patient characteristics are summarized in Table 1. A total of 37 patients were included in the present study, with a median follow-up of 1.5 years (range, 0.4–4.9). Of the 37 patients, 27 had adenocarcinoma (73%) and 10 had squamous cell carcinoma (27%). A total of 21 patients were treated with preoperative CRT (57%) followed by surgical resection, and 16 patients were treated with definitive CRT (43%) without resection. Nine patients had TRG 0 (43%), 6 had TRG 1 (29%), 2 had TRG 2 (9%),

Discussion

Although the optimal treatment approach for esophageal cancer remains controversial, CRT plays a major role. Recent studies using conventionally fractionated RT schedules and newer chemotherapy agents have demonstrated that preoperative CRT improves survival over surgery alone 2, 3. Additionally, two randomized trials have shown that the survival after CRT alone was similar to CRT followed by surgery 4, 5. Finally, survival was superior with CRT compared with surgery alone in a prospective

Conclusion

Our study has shown that MTV and TGA are predictive of the pathologic response and prognostic after CRT for esophageal cancer, and SUV alone might be of limited value. The MTV_2.5Post and TGA_2.5Post appear to best correlate with the disease outcome and pathologic response, and the rMTV_2.5 and rTGA_2.5 also correlated with pathologic response. Additional studies are needed to validate these findings. PET could potentially be used to guide therapy after CRT, such as determining the need for

References (27)

H. Ariga et al.
Prospective comparison of surgery alone and chemoradiotherapy with selective surgery in resectable squamous cell carcinoma of the esophagus
Int J Radiat Oncol Biol Phys
(2009)
P. Flamen et al.
Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer
Ann Oncol
(2002)
A.A. Konski et al.
Correlation of molecular response as measured by 18-FDG positron emission tomography with outcome after chemoradiotherapy in patients with esophageal carcinoma
Int J Radiat Oncol Biol Phys
(2007)
F. Lordick et al.
PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: The MUNICON phase II trial
Lancet Oncol
(2007)
J.D. Murphy et al.
Postradiation metabolic tumor volume predicts outcome in head-and-neck cancer
Int J Radiat Oncol Biol Phys
(2011)
D. Schellenberg et al.
18Fluorodeoxyglucose PET is prognostic of progression-free and overall survival in locally advanced pancreas cancer treated with stereotactic radiotherapy
Int J Radiat Oncol Biol Phys
(2010)
R.V. Scheer et al.
Quantifying the benefit of a pathologic complete response after neoadjuvant chemoradiotherapy in the treatment of esophageal cancer
Int J Radiat Oncol Biol Phys
(2011)
J.B. Roedl et al.
Adenocarcinomas of the esophagus: response to chemoradiotherapy is associated with decrease of metabolic tumor volume as measured on PET-CT: Comparison to histopathologic and clinical response evaluation
Radiother Oncol
(2008)
A. Jemal et al.
Cancer statistics, 2010
CA Cancer J Clin
(2010)
J. Tepper et al.
Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781
J Clin Oncol
(2008)

Gaast AV, van Hagen P, Hulshof M, et al. Effect of preoperative concurrent chemoradiotherapy on survival of patients...

M. Stahl et al.

Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus

J Clin Oncol

(2005)

L. Bedenne et al.

Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102

J Clin Oncol

(2007)

Cited by (55)

Circulating Tumor DNA Analysis for Detection of Minimal Residual Disease After Chemoradiotherapy for Localized Esophageal Cancer
2020, Gastroenterology
Biomarkers are needed to risk stratify after chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of additional therapy.
We performed deep sequencing (CAncer Personalized Profiling by deep Sequencing, [CAPP-Seq]) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes and fixed esophageal tumor biopsy samples collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy, and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy control individuals. We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6–8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) after chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy).
The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA after chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P < .0001), formation of distant metastases (hazard ratio, 32.1; P < .0001), and shorter disease-specific survival times (hazard ratio, 23.1; P < .0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P = .03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P < .001 for comparison of either technique to combined analysis).
In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.
Phase II study of metabolic response to one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma
2019, Journal of the Formosan Medical Association
In the treatment of esophageal squamous cell carcinoma (ESCC), the optimal use of ¹⁸fluorodeoxyglucose positron emission tomography (PET) in measuring metabolic tumor response is undetermined. We launched a phase II trial to evaluate early metabolic response to one-cycle induction chemotherapy in patients with locally advanced ESCC.
ESCC patients in stage classification T3N0, N1M0, or M1a (American Joint Committee on Cancer, 6th edition) received one-cycle chemotherapy comprising paclitaxel, cisplatin, and 24-h infusional 5-fluorouracil and leucovorin on days 1 and 8, followed by neoadjuvant chemoradiotherapy, 40 Gy, with paclitaxel/cisplatin and then esophagectomy. PET was performed at baseline and day 14 of chemotherapy. The primary endpoint was pathologic complete response (pCR). We hypothesized early metabolic responders with >35% reduction in maximum standardized uptake value (SUV_max), would have better pCR Results.
Sixty-six patients were enrolled. The median progression-free survival (PFS) and overall survival (OS) were 16 months (95% confidence interval [CI], 9–27) and 22 months (16–40), respectively. The early metabolic response rate was 55%; and the pCR rate was 34% in the esophagectomy population. The early metabolic response was not associated with pCR or survival. In an exploratory analysis, the postchemotherapy SUV_max was an independent prognostic factor for pCR, PFS, and OS.
Our study failed to validate the predefined early metabolic response for pCR to neoadjuvant chemoradiotherapy in locally advanced ESCC patients. However, postchemotherapy SUV_max may be prognostic and predictive, and warrants further study.
Patient-derived tumor organoids for prediction of cancer treatment response
2018, Seminars in Cancer Biology
Citation Excerpt :
Conversely, approximately 20% do not respond to neoadjuvant chemoradiotherapy (nCRT) and would probably benefit from early surgery [10,12] or alternative treatment. However, the current imaging tools (such as positron-emission and computed tomography (PET-CT) techniques) to identify these two patient groups prior to treatment are still unable to predict response with reliable accuracy [13–15], and as a result 25% of these patients either undergo unnecessary surgery or ineffective preoperative chemoradiotherapy (20%). Therefore, better models to predict the treatment response of esophageal cancer and other cancers with the required accuracy are essential towards a more individualized treatment of patients (Table 1).
Cancer treatment, in particular radiotherapy and chemotherapy, is often hindered by an inherent resistance of cancer cells. Cancer stem cells in particular have previously been shown to be more resistant than other cells within a tumor and are thought repopulate the tumour after therapies. Therefore, it is of utmost importance to develop tools and techniques that can be used to study mechanisms of resistance of cancer stem cells as potential treatment targets. Organoids (and cancer-derived organoids), are three-dimensional tissue-resembling cellular clusters derived from tissue or tumor specific stem cells that mimic the in vivo (tumor) characteristics, as well as (tumor) cell heterogeneity. Cancer organoids may further enhance the in vitro and in vivo models that are currently available, improve our understanding of cancer stem cell resistance and can be used to develop novel cancer treatments by improved targeting of cancer stem cells. In this review, we compare organoids with the more traditional laboratory models, such as cell lines and xenografts, and review the literature of the current role of cancer organoids in determining treatment responses.
Whole-body total lesion glycolysis is an independent predictor in patients with esophageal cancer treated with definitive chemoradiotherapy
2018, Radiotherapy and Oncology
Citation Excerpt :
TLGWB and MTVWB are thus a reasonable and appropriate predictor for the outcome of esophageal cancer. Past reports on MTV and TLG for esophageal cancer patients treated with dCRT are summarized in Appendix B [10–16]. Lemarignier, Li, Butof and Hong showed that MTV and/or TLG were independent predictors for outcomes in esophageal cancer patients treated with dCRT.
To determine whether pretreatment whole-body total lesion glycolysis (TLG_WB) and metabolic tumor volume (MTV_WB) are associated with outcomes in patients with esophageal cancer treated with definitive chemoradiotherapy (dCRT).
Ninety patients with stage II or III thoracic esophageal cancer who underwent FDG-PET/CT within 45 days before dCRT between 2005 and 2013 were reviewed. MTV and TLG of the primary lesion (MTV_pri and TLG_pri) and the sum of MTV and TLG for all lesions (MTV_WB and TLG_WB) were calculated. Predictors were analyzed using the Cox proportional hazards model.
The median follow-up period was 27.7 months. In multivariate analysis, MTV_WB > median was an unfavorable predictor for OS (p = 0.027, hazard ratio [HR]: 2.15), LC (p = 0.039, HR: 1.98) and PFS (p = 0.041, HR: 1.96). TLG_WB > median was an unfavorable predictor for OS (p = 0.019, HR: 2.26), LC (p = 0.015, HR: 2.36) and PFS (p = 0.014, HR: 2.33). SUV_max was not a predictor, and the HR of TLG_WB was higher than that of MTV_WB for OS, LC and PFS in multivariate analysis.
TLG_WB and MTV_WB are independent predictors in patients with esophageal cancer.
Esophageal cancer
2019, Medecine Nucleaire
Prognostic value of baseline <sup>18</sup>F-FDG PET/CT in patients with esophageal squamous cell carcinoma treated with definitive (chemo)radiotherapy
2023, Radiation Oncology

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: Conflicts of interest: none.

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Clinical InvestigationPostchemoradiotherapy Positron Emission Tomography Predicts Pathologic Response and Survival in Patients With Esophageal Cancer

Purpose

Materials and Methods

Results

Conclusion

Introduction

Section snippets

Methods and Materials

Results

Discussion

Conclusion

Int J Radiat Oncol Biol Phys

Ann Oncol

Int J Radiat Oncol Biol Phys

Lancet Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Cancer statistics, 2010

CA Cancer J Clin

Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781

J Clin Oncol

Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus

J Clin Oncol

Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102

J Clin Oncol

Clinical Investigation
Postchemoradiotherapy Positron Emission Tomography Predicts Pathologic Response and Survival in Patients With Esophageal Cancer