Metabolic response assessment and PET-guided treatment of esophageal cancer
Authors: F. Lordick, K. Herrmann
Journal: Annals of Oncology (2020)

Esophageal adenocarcinoma is an increasing global health problem in high income regions, with excess body weight and gastro-esophageal reflux disease among the key risk factors.1Bray F. Ferlay J. Soerjomataram I. et al.Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (50539) Google Scholar Despite important progress in the operative and perioperative management of this disease, survival outcomes remain poor.2Smyth E.C. Lagergren J. Fitzgerald R.C. et al.Oesophageal cancer.Nat Rev Dis Primers. 2017; 3: 17048Crossref PubMed Scopus (295) Google Scholar The optimal perioperative treatment regimen for an individual patient presenting with locally advanced esophageal adenocarcinoma is unknown. While phase III studies showed that neoadjuvant-treated cohorts of patients achieve better overall survival (OS) outcomes compared with surgery alone,3Allum W.H. Stenning S.P. Bancewicz J. et al.Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer.J Clin Oncol. 2009; 27: 5062-5067Crossref PubMed Scopus (740) Google Scholar,4van Hagen P. Hulshof M.C. van Lanschot J.J. et al.CROSS GroupPreoperative chemoradiotherapy for esophageal or junctional cancer.N Engl J Med. 2012; 366: 2074-2084Crossref PubMed Scopus (3562) Google Scholar the individual response to a specific neoadjuvant treatment regimen is unpredictable. Importantly, the stage of esophageal adenocarcinoma after neoadjuvant treatment determines prognosis.5Davies A.R. Gossage J.A. Zylstra J. et al.Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction.J Clin Oncol. 2014; 32: 2983-2990Crossref PubMed Scopus (182) Google Scholar Positron emission tomography (PET) imaging may differentiate responding and non-responding tumors early in the course of therapy. This approach was first established and also validated by the Munich investigators more than a decade ago.6Lordick F. Ott K. Krause B.J. 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; 8: 797-805Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 7Ott K. Weber W.A. Lordick F. et al.Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction.J Clin Oncol. 2006; 24: 4692-4698Crossref PubMed Scopus (404) Google Scholar, 8Weber W.A. Ott K. Becker K. et al.Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging.J Clin Oncol. 2001; 19: 3058-3065Crossref PubMed Scopus (631) Google Scholar Other study groups took up the concept and developed it further. Australian investigators were the first to publish their data in a full paper, which is presented in this issue of the Annals of Oncology. In the AGITG (Australasian Gastrointestinal Trials Group) DOCTOR study, patients with resectable esophageal adenocarcinoma received induction cisplatin and 5-fluorouracil (CF) and were assessed by PET. Patients with an early metabolic response (standard uptake value [SUV]max ≥35% reduction from baseline to day 15) were treated with another CF cycle and underwent esophagectomy. Non-responders were randomized 1 : 1 to either two cycles of CF and docetaxel (DCF) or DCF + 45 Gray radiotherapy, followed by esophagectomy. The primary endpoint was major histological response (<10% residual tumor) in the esophagectomy specimen; secondary endpoints included OS and locoregional recurrence.9Barbour A.P. Walpole E.T. Mai G.T. et al.Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.Ann Oncol. 2020; 31: 236-245Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar What did we learn from the DOCTOR study? First and foremost, early metabolic response assessment using sequential 18F-fluorodeoxyglucose (FDG)-PET can be successfully implemented in the curative treatment strategy of patients with esophageal cancer in a multicenter setting. The investigators must be commended for their effort to organize and conduct this complex investigator-driven and purely academic study. Secondly, DOCTOR confirms that early metabolic response is associated with better OS outcomes. Beyond that, DOCTOR suggests that the addition of docetaxel to conventional CF chemotherapy improves response and survival outcomes, thereby validating findings from the FLOT-4 study.10Al-Batran S.E. Homann N. Pauligk C. et al.Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.Lancet. 2019; 393: 1948-1957Abstract Full Text Full Text PDF PubMed Scopus (957) Google Scholar Thirdly, the addition of radiation to neoadjuvant chemotherapy leads to higher tumor response rates and lower local relapse rates. Whether this translates into better survival outcomes remains unclear, as the DOCTOR study was neither designed nor powered to show a survival benefit for preoperative radiochemotherapy versus chemotherapy. This important question will be answered in ongoing randomized controlled trials such as ESOPEC (NCT02509286) and NEO-AEGIS (NCT01726452). What are the weaknesses of the DOCTOR study? DOCTOR is a relatively small study involving no more than 66 metabolic non-responding patients. This underlines the difficulties of performing complex clinical research in this disease setting. Seven national expert centers needed 6 years to recruit this number of eligible patients. With this number of patients, it is almost impossible to demonstrate the true value of a novel strategy of care. Moreover, and having said that DOCTOR suggests beneficial effects of taxanes in the perioperative treatment, the taxane-containing FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) regimen has become the standard of care in the management of this disease. One may ask where the value of PET-response assessment is during FLOT perioperative treatment and which alternatives to FLOT we have beyond the addition of radiation therapy. However, going back to the times of the MUNICON studies, FLOT-like taxane-containing neoadjuvant therapy was already used in fit and younger patients6Lordick F. Ott K. Krause B.J. 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; 8: 797-805Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar and a non-metabolic response to FLOT was seen in some patients and was associated with worse survival outcomes. Another criticism could be that tumor regression grading (TRG) is an imperfect primary endpoint. The value of TRG to predict survival outcomes is controversial. While several studies suggest an association between TRG and OS, a recent retrospective study could not confirm that TRG is an independent prognostic marker. Lymph node metastases and not pathologic response to chemotherapy was the only independent predictor of survival after chemotherapy plus resection in a retrospective analysis of tumor material from the UK MAGIC study.11Smyth E.C. Fassan M. Cunningham D. et al.Effect of pathologic tumor response and nodal status on survival in the medical research council adjuvant gastric infusional chemotherapy trial.J Clin Oncol. 2016; 34: 2721-2727Crossref PubMed Scopus (173) Google Scholar Therefore, to see more ypN0 stages and better survival outcomes might be the more meaningful primary endpoint. Moreover, neither metabolic response nor TRG were assessed centrally in DOCTOR; some may find this necessary when PET is the novel tool to be assessed and histopathologic response is the primary endpoint. What are the perspectives for early response assessment in the management of localized esophageal cancer? In the near future, we are expecting more publications referring back to the MUNICON concept. However, neither CALGB-80803 (NCT01333033) nor MEMORI (EudraCT 2014-000860-16), SCOPE2 (NCT02741856), and GastroPet (EudraCT 2017-001264-38) are designed to provide definitive answers on the value of early metabolic response assessment. All designs are more or less exploratory. Is it time to design a randomized controlled study that allocates metabolic non-responders to a continuation of the same (unaltered) neoadjuvant standard treatment and compare it with an altered treatment, whether it be de-escalated or escalated therapy? Alternatively, patients could undergo randomization between PET-tailored therapy versus a non-PET-guided treatment approach. Admittedly, such designs would require a huge number of patients to be sufficiently powered. Before we embark on this, we need a clear hypothesis of what we expect from a novel approach as compared with the standard of care. As long as we do not have this excellent and compelling hypothesis, we may use early metabolic response assessment for smaller, exploratory studies to assess novel drugs and combinations in the perioperative treatment of localized esophageal cancer. In summary, the DOCTOR investigators demonstrated that early metabolic response is associated with favorable survival outcomes. For non-responders, the addition of docetaxel augmented histological response rates and survival outcomes while local relapse rates remained inferior when compared with responders. The addition of radiation improved histological response and lowered local relapse rates, but whether it also improves OS remains unknown. We agree that early PET-based response assessment has the potential to tailor therapy for patients not showing an early response to chemotherapy. But it is not yet ready for daily practice outside of clinical trials because the question of what the best approach for early metabolic non-responders remains unanswered today. None declared.