- Email: [email protected]
A rationale multidisciplinary approach for treatment of esophageal and gastroesophageal junction cancer: Accurate review of management and perspectives
Accepted Manuscript Title: A rationale multidisciplinary approach for treatment of esophageal and gastroesophageal junction cancer: accurate review of management and perspectives Authors: Antonio Chiappa, Bruno Andreoni, Renzo Dionigi, Lorenzo Spaggiari, Diego Foschi, Gianluca Polvani, Roberto Orecchia, Nicola Fazio, Gabriella Pravettoni, Maria Laura Cossu, Domenico Galetta, Marco Venturino, Carlo Ferrari, Lorenzo Macone, Cristiano Crosta, Bernardo Bonanni, Roberto Biffi PII: DOI: Reference:
S1040-8428(17)30325-6 https://doi.org/10.1016/j.critrevonc.2018.10.002 ONCH 2632
To appear in:
Critical Reviews in Oncology/Hematology
Received date: Revised date: Accepted date:
29-6-2017 22-9-2018 9-10-2018
Please cite this article as: Chiappa A, Andreoni B, Dionigi R, Spaggiari L, Foschi D, Polvani G, Orecchia R, Fazio N, Pravettoni G, Cossu ML, Galetta D, Venturino M, Ferrari C, Macone L, Crosta C, Bonanni B, Biffi R, A rationale multidisciplinary approach for treatment of esophageal and gastroesophageal junction cancer: accurate review of management and perspectives, Critical Reviews in Oncology / Hematology (2018), https://doi.org/10.1016/j.critrevonc.2018.10.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A rationale multidisciplinary approach for treatment of esophageal and gastroesophageal junction cancer: accurate review of management and perspectives
IP T
Running title: Treatment of esophageal and gastroesophageal junction cancer in the era of multidisciplinary approach
SC R
Antonio Chiappa1, MD, F.A.C.S., Bruno Andreoni2, MD, Renzo Dionigi3, MD, F.A.C.S., F.R.C.S. (Hon Ed), Lorenzo Spaggiari4, MD, Diego Foschi5, MD, Gianluca Polvani6, MD, Roberto Orecchia7, MD, Nicola Fazio8, MD, Gabriella Pravettoni9, MD, Maria Laura Cossu10, MD, Domenico Galetta4, MD, Marco Venturino11, MD, Carlo Ferrari1, MD, Lorenzo Macone2, 1, Cristiano Crosta12, MD, Bernardo Bonanni13 MD, Roberto Biffi14, MD
Unit of Innovative Surgical Techniques-University of Milano and European Institute of Oncology-ITALY Unit of Innovative Techniques in Surgery European Institute of Oncology University of Milan – ITALY
2
University of Milan Milan – ITALY
3
Department of Surgery University of Insubria Varese – ITALY
4
Department of Thoracic Surgery European Institute of Oncology University of Milan – ITALY
5
Department of Surgery “Luigi Sacco” Hospital University of Milan – ITALY
6
Cardiothoracic Surgery “Monzino” Cardiologic Institute University of Milan – ITALY
7
Department of Radiotherapy European Institute of Oncology University of Milan – ITALY
8
Unit of Medical Oncology European Institute of Oncology Milan – ITALY
10
N A M ED
PT
Unit of Psycho-Oncology European Institute of Oncology University of Milan – ITALY Division of General Surgery II University Hospital of Sassari; Department of clinical and Trial Medicine University of Sassari – ITALY Division of Anaesthesiology European Institute of Oncology Milan – ITALY
A
11
CC E
9
U
1
12
Division of Endoscopy European Institute of Oncology Milan-ITALY
13
Division of Cancer Prevention European Institute of Oncology Milan – ITALY
14
Division of Digestive Tract Surgery European Institute of oncology Milan – ITALY
1
Corresponding Author and address: Antonio Chiappa, MD, F.A.C.S. Dept of General Surgery-University of Milano European Institute of Oncology Via G. Ripamonti, 435 20141 – MILANO – ITALY Email: [email protected] Email: [email protected]
Abstract:
PT
ED
M
A
N
U
SC R
IP T
Graphical abstract
Cancer of the esophagus and of gastroesophageal junction can be cured, even if with lacking cure rate. Different
CC E
approaches have been developed, mostly when carcinoma has loco-regional pattern. Multimodality therapy showed a survival rate superior than 10% if compared to a single approach. This is a systematic review, carried to assess the following matters: Which therapeutic opportunities are available? Who could benefit of them? Which adverse reactions could possibly verify? How can physicians definitely choose the proper strategy? Which is the role of surgery? We
A
mean to give either General Practitioner or specialists clear and efficient updates about current treatment of this tumour, starting from physical examination. Four eminent guidelines were consulted for our study: Cancer Care Ontario’s Program in Evidence-Based Care, NCCN, Belgian Health Care Knowledge Centre and Esmo.
Abbreviations used in the text: NCCN: National Comprehensive cancer Network; SCC: Squamous Cell carcinoma; UICC: Union for International Cancer Control; EGJ: Esophagogastric junction; CCO: Cancer Care Ontario Program; OS: Overall Survival; CRT: Chemo-radiotherapy; CT: chemotherapy; RT: radiotherapy; 5-FU: 5-Fluorouracil.
2
1
Introduction The Globocan 2012 asserted that cancer of the esophagus is the eighth most common cancer worldwide, sixth
for mortality, with approximately 496,000 cases in 2015. Less developed countries are most likely to develop this disease (80%), although incidence is truly variable worldwide [1]. Despite the fact that the survival rate has been slowly increasing in the U.S.A. by around 0.7% per year (2002-2012), perhaps after the adhesion to multimodality techniques for treatment and improved supportive care, the worldwide survival rate has not been superior to 18.8% at 5 years yet [2]. Nevertheless, the fundamental principle to treat this cancer remains a “tailored” therapy, based on comorbidities. The two predominant histological subtypes of esophageal cancer are adenocarcinoma and squamous cell
IP T
carcinoma (SCC). The UICC-TNM stages provide useful prognostic parameters, which differ slightly between histological subtypes [3]. As, historically, squamous cell carcinoma (SCC) and adenocarcinoma are believed to have similar clinical progression, they are assumed as a single entity. Recent Authors assert that cytology, histology and therapy
SC R
efficacy should be the keystones of management. Furthermore, local lymphatic involvement seems to have an important role in surgical and radiotherapy strategy planning.
The incidence of esophageal cancer does not seem to decrease (16,940 new cases estimated [2]), probably due to increasing incidence of adenocarcinoma of the lower third of the esophagus and of the esophagogastric junction (EGJ).
U
Cancers of EGJ are defined as those that arise within 5 centimeters of the anatomical cardia. Siewert type I EGJ tumours
N
has their centre located between 5 and 1 cm proximally to anatomical cardia. They usually arise from an area of Barrett’s metaplasia in the lower esophagus and infiltrate the EGJ distally; Siewert type II tumours arise at the true cardia
A
immediately at the EGJ, and type III tumours originate in the subcardial area (2 to 5 cm distally) and infiltrate the EGJ
Siewert Classification
ED
Type 1
M
proximally [4, Figure 1].
Anatomical site of tumour centre
5 cm – 1 cm proximally to anatomical cardia Cardia (“pure” junctional tumour)
Type 3
2-5 cm distally to anatomical cardia
PT
Type 2
Figure 1. The Siewert classification: EGJ tumours are classified in relation to their anatomical site.
CC E
The clinical management of malignancies of the gastroesophageal junction (EGJ) is currently one of the most challenging scientific issues. To classify junctional tumours, we refer to the 7th edition of the Union for International Cancer Control (UICC) TNM staging system. In this study, tumours with an epicentre within 5 centimeters of the EGJ and extend into the esophagus are classified and staged using the esophageal system [3].
A
The present study deals with some important issues, critical in clinical decision-making, from examination to treatment of patients: -
Which therapeutic opportunities are available?
-
Who could benefit of them?
-
Which adverse reactions could possibly verify?
-
How can physicians definitely choose the proper strategy?
-
Which is the role of surgery?
3
These questions should find their own answer in this article, through the studies that we mean to mention. Our aim is to clarify the attitude a multidisciplinary board should have in order to treat esophageal cancer with curative intent.
2
Methods We discuss data from available clinical trials, meta-analyses and guidelines in the non-surgical treatment of
resectable esophageal and EGJ cancer. The electronic database PubMed was searched (since August 2015) and we selected several trials (randomized, non-randomized, prospective, multicentred, etc.), but only randomized trials and
IP T
systematic reviews were used to provide evidence-base conclusions. Four guidelines (since 2012) has been used: the Cancer care Ontario’s Program in Evidence-Based Care (CCO PEBC) has a good AGREE score [5, 6, 7]. The National Comprehensive Cancer Network (NCCN) recruited appreciable and reliable sources [8]. The Belgian Health Care
SC R
Knowledge Centre (KCE reports 179A) used the GRADE methodology and nomenclature [9, 10]. The new 2016 ESMO clinical practice guidelines represent the latest management indications available and supply an efficient and current summary to approach this disease, provided by a board of eminent and expert researchers [11]. Recommendations from the previously mentioned guidelines were evaluated. A really well conducted 2015 review by Jang et al. was considered for our study [12]. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for
U
systematic reviews were used for our study [13].
N
An overview of the amount and the years of the studies we have consulted is reported in Table 1. They are
Guidelines
4
2003 - 2016
Trials
51
1988 - 2017
21
1988 - 2017
Meta-analyses
10
1998 - 2014
Reviews
6
2004 - 2016
Randomized
3
CC E
Table 1. Studies consulted.
PT
-
M
Years
ED
N°
A
mentioned all over in the text.
Results
Non surgical techniques for the treatment of esophageal cancer
A
As surgery is the common treatment of choice in local disease, several issues arise when discussing advanced
disease. While adjuvant therapy has a consolidated role in treating cancer, neoadjuvant therapy has recently gained consideration in clinical practice. There are many trials, meta-analyses and systematic reviews (mentioned by CCO PEBC guidelines too). Two additional randomized trials [14, 15], and 7 meta-analyses and systematic reviews were published after CCO PEBC guidelines [16-22]. ESMO guidelines mention several and meta-analyses that we used for our study. Additionally, ESMO team included a meta-analysis by Kranzfelder et al. [23] and a retrospective multi-centre study carried by Markar et al. [24] both assessing the role of neoadjuvant therapy. All trials, meta-analyses and reviews are mentioned in our “References” section.
4
Several attempts to improve outcomes arouse, including neoadjuvant CRT, peroperative chemotherapy, exclusive-definitive CRT, and adjuvant CRT. Concerning the current literature, none of them is accompanied by strong evidences of better outcomes neither in the 5-year survival, nor in the R0 resection. The techniques and the related results in clinical trials are the following. Preoperative CRT and perioperative chemotherapy Multiple strategies including preoperative CRT, peroperative chemotherapy alone, exclusive CRT, and adjuvant
IP T
CRT in advanced esophageal cancer, symbolise the effort to improve outcomes in advanced cancer of the esophagus.
The assessment of preoperative CRT originates from a total of several randomized trials [14, 23-36], while the
SC R
two most recent voices are the critical CROSS trial (2012) [32] and FFCD 9901 trial (2014) [14].
A 2004 review [37] including different meta-analyses stated that trials analyzing this strategy were quite equivalent. The main result was a survival improving at 3 years [38-41]. A meta-analysis included results from the CROSS trial and confirmed the survival benefit of neoadjuvant CRT over surgery alone (hazard ratio (HR), 0.78; 95% CI, 0.70-
U
0.88; p<0.0001), estimated as 8.7% at 2 years [42].
N
The CROSS trial [34] consisted of 366 patients with either adenocarcinomas or EGJ cancers and was the widest single-study trial of preoperative CRT versus surgery alone. Patients were randomized in two groups: the first one
A
received 41.4 Gy of radiotherapy (duration: 5 weeks) with simultaneous weekly carboplatin and paclitaxel (50 mg/m2)
M
followed by surgery; the second group had only surgery. Macro- and microscopic pathologic complete response was completed in 29% of treated patients. Eventually, the preoperative CRT group had better cancer specific survival. (HR of 0.657, 95% CI, 0.495-0.871; p=0.003). The overall cancer specific survival advantage at 5 years was approximately 13%.
ED
Low rates of loco-regional recurrences and metastases were reported [43]. FFCD 9901 randomized trial enrolled patients with early-stage (stages I and II) esophageal cancer with
PT
histological evidence. Two arms were set: one composed by patients undergone CRT (45 Gy in 25 fractions for 5 weeks with 2 cycles of simultaneous chemotherapy with 800 mg/m2 of fluorouracil and 75 mg/m2 of cisplatin) followed by surgery; another one who received surgery only. Overall survival curves for the 2 arms resulted in a crossing at 3 to 4
CC E
years. The combined arm showed a higher survival rate after 4 years. As also Shapiro and colleagues [44] observe, the higher postoperative complications rate in combined arm (11.1% vs 3.4%, p=0.02) could be the effect of a low case volume in the centres enrolled in this trial (195 patients in 30 centres in 9 years). Czito and colleagues [45], as Shapiro,
A
suggest that a possible underlying cause of this rate could be the quality of chemoradiotherapy regimens too. However, integrating these data and applying them to eligible patients, combined therapy seems to provide a
survival advantage, resulting a suitable treatment strategy, mostly in II stage cancer. CROSS trial remains the leading reference, concerning its methods and results. Neoadjuvant chemotherapy
5
Data concerning the trial mentioned so far suggested that the proportion of patients completing the postoperativeadjuvant regimen is limited, with a consistent part of the benefit from the perioperative treatment attributable to the preoperative-neoadjuvant component. Some authors [19, 42] recently realised a meta-analysis of trials concerning the neoadjuvant treatment of esophageal cancer and revealed an improved survival, with an HR of 0.87 (95% CI, 0.79-0.96; p=0.005). Preoperative chemotherapy with surgery was studied in several randomized trials [25, 46-55]. Yet, three other trials focused on the benefit of perioperative chemotherapy [56-58].
IP T
This regimen of treatment has been often supported in various studies dealing with perioperative esophagus cancer chemotherapy. We have some data about 36 patients in a study by Roth and coworkers, but, although the randomization, the sample was too small to produce reliable recommendations [56]. Regarding this, two important voices
SC R
were Kelsen and Ychou. Kelsen led a US Intergroup trial (RTOG 8911, US Intergroup 113) in 2007 with 467 cases [55, 57]. Ychou carried a trial in 2011 in which 224 patients participated [54]. The design of these two studies was similar (regimen based on cisplatin plus fluorouracil). Nevertheless, the results were different: only the trial of Ychou had positive results. This disproportion could be related to the higher presence of advanced cancers in the US trial (10% weight loss at diagnosis was about 23% and R0 resection was 60%). It is not unusual that a heterogeneous recruitment may cause
U
such different data.
N
In contrast, Cunningham and his trial, dealing with the single perioperative chemotherapy for gastric cancer [59],
A
including lower esophagus and EGJ adenocarcinomas (25%), was important in changing clinical practice. A significant
the sample was wide enough.
ED
Neoadjuvant chemoradiotherapy, is it possible?
M
5 years overall survival benefit with perioperative chemotherapy versus surgery alone was reported (36% vs 23%) and
Another issue remains open: why and when neoadjuvant CRT versus neoadjuvant chemotherapy alone in adenocarcinomas? Unfortunately, two randomized trials attempting to clarify this debate failed to provide a proper answer
PT
[60, 61].
Stahl and coworkers reported a single-phase III trial (known as POET trial) comparing these strategies [60]. It
CC E
included 126 patients with equal proportion of Sievert I and II/III adenocarcinoma of the EGJ. The study was early closed because of poor accrual and results did not gain statistical significance. However, the study evidenced a 3 years absolute survival rate that supported preoperative CRT (47.7% vs 27.7%). Burmeister et al. in his study [61] reported no difference in survival between the two techniques, but remarked
A
an improvement in margin involvement with the addition of radiotherapy. The trial was conducted on 75 patients with esophagus/EGJ adenocarcinomas smaller than 2 cm. The choice of the adequate strategy must be guided by clinical experience and the presence of comorbidities. The extent of the tumour, especially in the cranio-caudal direction, may expose a significant portion of lungs and heart to massive doses of radiation. Preoperative chemotherapy without radiotherapy may be preferred when nodal involvement exceeds the target volume or in presence of significant primary tumour length. In the CROSS trial were included only patients with a cancer extension (either cranio-caudally or laterally) within 8 cm [34]. nCRT seems suitable to patients who have a major lateral involvement by tumour. Assuming R0 resection and histopathological complete response
6
evidence as intermediate outcome, nCRT results in an advantage for these patients. This could highlight the importance of the radiotherapeutic component in down-staging the cancer. For gastro-esophageal tumours invading the gastric cavity, a higher pattern of nodal spread has been evidenced, as for gastric cancer. The usual radiotherapy settings employed in the current trials are designed to include peri-esophageal nodes. Perhaps radiotherapy might be the discriminating factor, which could enhance, at the same time, the treatment of the lesion itself and of the nodes too. The debate about toxicity is, therefore, worthy. Toxicity is an intermediate end-point in TOPGEAR trial [62] (see below in “Toxicity”). Concerning some authors [63, 64], postoperative CRT is not a recommended option for patients with esophageal cancers that are above the EGJ, but only for those with a clear EGJ cancer.
IP T
Although they are not properly recent data, reliable evidences carried by Teniere and Arnott [65, 66] demonstrate a lack of survival benefit with radiotherapy alone (either preoperative or postoperative). On the other hand, there is lack
SC R
of data to choose exclusively adjuvant chemotherapy. Definitive CRT versus CRT with or without surgery
Two important resources in treating this cancer are definitive CRT and combined modality with surgery. The first one is usually reserved to those with several comorbidities or who express a clear refusal of surgery. Squamocellular
U
cancer is becoming more in more unresectable (although further studies are needed to give it significative evidence). By contrast, surgeons and geriatric specialists are not considering advanced age as a contraindication anymore. Actually, in
N
clinical practice, we witness even elderly patients undergoing esophagectomy.
A
Wong realised in 2006 a cochrane review (updated and withdrawn in 2010) in which he stated that, when a non-
M
operative approach is chosen, concomitant RCT is better than RT alone for patients with localized esophageal cancer but with significant toxicities [67]. However, if physical status is not particularly compromised, CRT may be applied as well.
ED
Definitive CRT was first evaluated in the RTOG 85-01 study [68] on 129 patients with localized (T1-3N0-1M0) esophageal SCC or adenocarcinoma. The study demonstrated an improved 5-year OS of 26% in patients randomized to four cycles of cisplatin 75 mg/m2 (day 1) and 5-FU 1000 mg/m2/day (days 1-4) with radiotherapy (50 Gy) compared with
PT
0% in those randomized to radiotherapy (64 Gy) alone. In the subsequent nonrandomized part of this study, a modest 5year OS of 14% was reported in the 73 patients assigned to CRT. Persistence of disease was most common in patients treated with radiotherapy alone (37% vs 25-28% with CRT). No further deaths due to esophageal cancer were observed
CC E
after 5 years. They asserted found the 8 years OS was 22% of the combined randomized group, suggesting that a proportion of patients can be really cured with CRT alone, not merely palliated for a longer time. In the attempt to reduce the persistence of local disease and reduce rates of loco-regional failure, the subsequent
A
RTOG 94-05 trial, investigated intensification of radiation therapy to 64.8 Gy with the same chemotherapy regimen used in RTOG 85-01, compared with chemotherapy plus the standard radiation therapy (50.4 Gy) [69]. This randomized phase III trial enrolled 236 patients with localized (T1-4 N0-1 M0) SCC or adenocarcinoma, of whom over 80% had SCC. No benefit in 2-year survival was demonstrated (2-year OS 31% vs 40% with standard CRT) and similar local persistence and loco-regional failure rates were observed in both arms. By contrast, treatment-related mortality was greater in patients randomized to the higher radiotherapy dose, showing a quite narrow therapeutic index. It is necessary, therefore, that a proper balance is assessed between efficacy and toxicity.
7
The relative benefit of definitive CRT over a purely surgical approach was evaluated in a small study including 80 patients with SCC who were randomized to definitive CRT with cisplatin 60 mg/m2 (days 1 and 22), infused fluorouracil 200 mg/m2/day (days 1-42) with radiotherapy (50-60 Gy) or surgery alone. No significant difference in median disease-free survival (20 vs 24 months with surgery) or 2-year OS (58.3% vs 54.5% with surgery) was reported at a median follow-up of 16.9 months [70]. However, the perioperative mortality rate in the surgery group was 6.8%. Six patients in the CRT arm underwent salvage surgery for persistent or recurrent disease, in which the perioperative mortality was 16.7%. However, surgery alone would not be considered a standard approach, due to complications; therefore a comparison of definitive CRT with neo-adjuvant CRT was made.
IP T
Nowadays, cisplatin and fluorouracil are considered the cornerstone. Conray et al. compared fluorouracil plus cisplatin and radiotherapy with FOLFOX regimen and radiotherapy, finding comparable survival rates [71]. Side reactions were slightly different. Merten et al., by contrast, focused on a carboplatin and paclitaxel plus a 50.4 Gy radiotherapy approach in locally unresectable patients [72]. That was judged as a tolerable regimen, leading to durable loco-regional
SC R
control and palliation in nearly half of patients, although a little amount of side effects occurred. 2 and 3-year survival were, respectively, 32% and 16%. Ruppert and Wang also experimented this approach [73, 74]. Definitive CRT versus surgery alone
U
We have only non-statistically significant data about CRT alone (definitive) versus surgery alone. In the study
N
carried by Teoh, 5-year OS was 50% with definitive CRT (vs 29% with surgery alone) and similar results were seen in
A
disease-free survivals [15].
M
Neoadjuvant CRT versus definitive CRT
Trials comparing preoperative CRT followed by surgery versus definitive CRT have been done mostly with SCC
ED
[75 ,76].
The first one by Stahl et al. used a regimen of induction CT plus CRT plus surgery plus RT (total dose 65 Gy) [75]. In the second trial by Badenne et al. (89% of SCC) the responsive patients after induction CT were randomized in
PT
two groups: one had further CRT and the other one received surgery [76]. These 2 trials had equivalent design. Results are the following: Stahl had an OS at 2 years of 33.6% for preoperative CRT and 39.8% for CRT alone; local control rate at 2 years was better in surgery arm (64.3% vs 40.7%). Baden had an OS at 2 years of 39.9% for preoperative CRT and
CC E
35.4% for CRT alone; local control rate at 2 years was still better in surgery arm (66.7% vs 57.0%). Surgery had, however, more complications.
There is need of further analyses, as all these studies used different regimens from the commonly used.
A
Salvage surgery
It is not uncommon, in oncology, to treat too painful discomforts or terminal conditions with surgery. For
instance, in lower gastrointestinal tumours or in pelvic diseases spread to the entire cavity, surgeons usually perform an ileostomy in order to canalize patients or to avoid occlusions. In esophageal cancer, this may be referred to dysphagia or airways involvement. In his study, Ariga and colleagues focused on the role of salvage surgery in a group of selected patients with thoracic esophageal squamocellular cancer [35]. 5-year OS was 75.7% in the CRT-alone arm and 50.9% in surgery arm. Of the first group, 25.5% had salvage esophagectomy. CRT was, thus, comparable or superior to salvage surgery.
8
Unfortunately, we have data only for patients with SCC, not for adenocarcinomas. The correct strategy to evaluate responses require further investigation, with regular and strict intervals of follow-up, although CRT alone seems to be a suitable approach in these cases. Toxicity In perioperative treatment, gastrointestinal and hematologic toxicities predominate. Possible gastrointestinal side effects are: nausea, vomiting, dysphagia, esophagitis, anorexia, diarrhea, etc. As for hematopoietic system: neutropenia, anemia, leukopenia, thrombocytopenia, etc. There are some possible complications during or after surgical operation:
IP T
anastomotic leak, intra-abdominal sepsis, wound infection, chest infection, respiratory failure, cardiac ischemia, etc. Toxicity of this technique is examined in the TOPGEAR trial that means to be a useful to guide clinical practice (Clinical Trials.gov identifier: NCT01924819). The interim analysis was recently published [62], demonstrating that
SC R
preoperative chemoradiotherapy is a safe procedure without increase in treatment toxicity. Further data about survival improving are expected at the end of the trial. That is one of the most pivotal trials dealing with this disease, mostly due to its relevant sample. These factors should be considered when selecting between these two modalities in the management of adenocarcinomas of the esophagus and EGJ. The rationale is to use chemo-radiotherapy in neoadjuvant setting,
U
switching to chemotherapy alone if adverse events (i.e. toxicities) develop.
N
On-going trials and the future
TOPGEAR trial has been discussed above. Several other trials dealing with this issue are being carried. We
Neoadjuvant Chemotherapy Versus Radiochemotherapy for Cancer of the Esophagus or Cardia
M
A
mention the most relevant to our study.
(NeoRes) (ClinicalTrials.gov Identifier: NCT01362127)
ED
This is an active non-recruiting trial, conducted by Nilsson et al. (Karolinska University Hospital) which enrolled 180 patients. The outcomes are, firstly, to evaluate wheter nRCT gives higher complete histological response after resection (14-16 weeks after therapy) than CT alone, secondly, to assess
PT
safety profile. The estimated study completion date is June 2018. Preoperative Concurrent Chemoradiotherapy for Locally Advanced Gastroesophageal Junction or Upper Gastric Adenocarcinoma (ClinicalTrials.gov Identifier: NCT02193594)
CC E
This study is still recruiting (214 patients enrolled within the period January 2014 – September 2017). The corresponding researcher is Jiafu Ji and it is carried mostly in Beijing Cancer Hospital. Primary outcome is therefore 3-year survival time and recurrence free survival. Other outcomes include complications rate, pathological responses, etc. The estimated study completion date is May 2020.
A
Perioperative Chemotherapy Compared To Neoadjuvant Chemoradiation in Patients With Adenocarcinoma of the Esophagus (ESOPEC) (ClinicalTrials.gov Identifier: NCT02509286) This study is still recruiting (438 patients enrolled within the period January 2016 - October 2017). The responsible researcher is Prof. Hoeppner and the study is multi-centred, with main setting in Freiburg University Hospital. Outcomes are, firstly, the overall survival; secondly, progression free survival time, failures, recurrence free survival time, quality of life, etc. The study will end in June 2023.
PDL-1 Targeting in Resectable Oesophageal Cancer (PERFECT) (ClinicalTrials.gov Identifier: NCT03087864)
9
This study is still recruiting (40 patients enrolled within the period January 2017 – March 2017). The corresponding author is van Laarhoven (Academisch Medisch Centrum, Universiteit van Amsterdam). Although the limited sample, this study has an ambitious purpose, i.e. to assess the role of target therapy combined to CRT in preoperative phase. Other outcomes concern safety, toxicity, etc. The study is estimated to finish by 2019. Of course we are all waiting for these studies to complete, in order to have further data, which could eventually define the role of nCRT in clinical practice. Despite the feasibility of target-therapy trials is not easy (mostly due to few and compromised patients enrolled), we look at them with confidence. All these data would be really
4
IP T
useful in strengthen esophageal cancer management. Recommendations
SC R
The Ontario panel recommended preoperative CRT with platinum based CT for resectable esophageal cancer. Preoperative platinum based CT alone may be an alternative. These guidelines suggest that for SCC with too high clinical risk, the non-surgical and conservative method is preferable, on the basis of current data [5, 6].
NCCN panel guidelines affirm that patients with localized esophago-gastric cancer benefit from combined
U
modality therapy. Multidisciplinary approach remains a cornerstone, with regular meetings to facilitate decisions, collegial review of data and the need for a special board that could discuss the case thoroughly. According to the
N
guidelines, CRT alone is indicated for T4b (non-resectable) tumours in good clinical status and for resectable tumours
A
(T1bN+, T2-4aN0-N+) in non-clinically stable patients. Medically fit patients with resectable tumours (T1bN+, T2-4aN0N+) should have CRT alone if cervical SCC esophageal cancer is present or for adenocarcinoma cases which refuse
M
surgery [8].
The Belgian guidelines reiterate the importance of multidisciplinary discussion. Neoadjuvant CRT is the
ED
treatment of choice for locally advanced esophageal tumour, with the board consensus. An adjuvant treatment is not habitually recommended. Definitive exclusive CRT should be considered in cases of locally advanced esophageal cancer,
PT
if the tumour is unresectable or the patient is not fit for surgery. No matter which histology belongs to the tumour [9]. The ESMO guidelines state that surgery remains the treatment of choice in limited disease and that nCRT does not improve R0 resection rate (II, B recommendation). If patients are unable or unwilling to receive surgery, then,
CC E
combined CRT is superior to RT alone (II, A recommendation). For locally advanced disease (T3-4, N1-3, M0): adenocarcinomas (considered like gastric tumours) should receive perioperative CT or preoperative CRT (I, A recommendation); SCC should receive nCRT with planned surgery or definitive CRT with close surveillance and salvage surgery for local tumour persistence or progression (II, B recommendation). Metastatic disease should be addressed to
A
palliative treatment [11].
An integrated approach of the above-mentioned guidelines is mandatory. The gist is that resectable tumours
should however undergo surgery, although CRT alone is sometimes a clinical choice. Neoadjuvant CRT is considered the goal; however, selective use of perioperative CT for adenocarcinomas is indicated when RT use is expected to be associated with increased toxicities.
5
Conclusions
10
Based on the current reported data from randomized controlled clinical trials and meta-analyses, definitive concurrent CRT using cisplatin and 5-FU is a useful treatment strategy in SCC of the esophagus, with surgery reserved as a salvage procedure in patients with persistent disease or for those who relapse. However, neoadjuvant CRT followed by surgery remains a valid option, especially for cases at lower surgical risk with an absence of several medical comorbidities, for either SCC or adenocarcinomas. Preoperative platinum-based chemotherapy plus radiotherapy is the preferred modality for the management of surgically resectable loco-regional esophageal cancer. Avoiding RT is still a
ED
M
A
N
U
SC R
IP T
valid choice.
A
CC E
PT
Figure 2. Algorithm for the treatment of local/locoregional resectable thoracic esophageal cancer. EUS, endoscopic ultrasound; FDG-PET, fluorodeoxyglucose-positron emission tomography; MS-CT, multislice-computed tomography; cTNM, clinical tumour, node, metastases classification according to AJCC/ UICC; CRT, chemoradiotherapy; OS, overall survival. 1 Criteria for endoscopic instead of surgical resection are specified in the text. 2 For patients unable or unwilling to undergo surgery, combined CRT is superior to radiotherapy alone. 3 Evidence suggests that neoadjuvant CRT followed by surgery and definitive CRT are equally effective with regard to overall survival. Oesophageal surgery should be carried out in experienced (high volume) centres only. For patients not willing to undergo oesophageal surgery or who are medically unfit for major surgery, definitive chemoradiotherapy should be preferred. Even many experienced centres prefer definitive CRT for oesophageal tumours with a very proximal/cervical location. 4 Sufficient evidence supports the use of perioperative chemotherapy as well as neoadjuvant CRT. Both standards can be recommended with an equal level of evidence/grade of recommendation [I, A]. Several ongoing studies in Europe are comparing both modalities. Inclusion of patients in one of these studies is encouraged. Some centres prefer neoadjuvant CRT for tumours of the oesophagus and AEG type I or II according to the Siewert’s classification, while they use perioperative chemotherapy for AEG type III or II, but this is only a pragmatic solution not currently supported by scientific evidence. 5 This is optional in the case of incomplete response to CRT or local relapse. This should be carried out only in selected patients and experienced centres. Lordick F et al. for the 2016 ESMO Clinical Practice Guidelines [11] elaborated the image. With curtesy of Oxford University Press, order n°: 4210960780868.
The treatment of breast, colon, and lung cancers, as well as hematological malignancies, has successfully made the transition towards personalised medicine by the incorporation of targeted agents for molecular selected patients into routine treatment strategies. The ToGA trial [77] has demonstrated that this is also possible in esophagogastric cancer, although further improvements in survival remain urgently needed. By designing studies with translational correlates, using molecular selection for new-targeted agents and including all willing and eligible patients in these trials, the effects
11
of targeted therapy can be evaluated in a rigorous and significant way in esophageal and EGJ cancers. HER2 receptor is, nowadays, the only target thoroughly studied for this cancer, because it is often associated to gastric cancer. The new development of personalised medicine, however, sheds new light on the role of psychological aspects on clinical outcomes, which are better in patients who are involved in the decision making process [78]. To maximise the effect of therapies, hence, a clinician must not only consider non-clinical aspects that can affect choices, but also the importance to optimise patient empowerment for improving adherence and treatment outcomes [79, 80]. At the moment, as we also can notice with a comparison with other eminent reviewers, innovation is that “there is no innovation” in treating esophageal and EGJ cancer. Of course, we are all waiting for results from above-mentioned
IP T
trials, although targeted and molecular therapy, in a reasonable point of view, will have future supremacy. In 2011, Hingorani et al. showed uncertainty about several different trials arising to deal with this disease, mostly due to contrasting data and, perhaps, non-standardized designs [81]. In that moment, they highlighted the necessity of direct comparison between the accredited therapies. We have remarked enough in this article the current results concerning this disease, and
SC R
we think that current on-going trials are following the right path.
As for as we are concerned, the algorithm [Figure 2] published with last ESMO guidelines [11] is, nowadays, the most useful tool for the management of esophageal cancer, applicable by GP during regular examination, up to the
N
U
specialists in the hospital.
A
Statements and disclosures
M
All the phases of the work have been carried on with the approval of the ethic committee and under the edge of a written consensus to use clinical and biomedical data for scientific purposes, signed by patients
ED
during pre-hospitalization visit.
All Authors have taken part to all stages of this work, design, execution, analysis.
PT
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
A
CC E
There is no financial interest neither any conflict of interests in the whole work
12
References [1].
Globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed October 11, 2017
[2].
Surveillance, Epidemiology, and EndResults Program. SEER Stat fact Sheets: esophageal cancer. Available at: http://seer.cancer.gov/statfacts/html/esoph.html. Accessed October 11, 2017
[3].
Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM classification of malignant tumors. 7 th edition. Oxford,
[4].
IP T
England: Wiley-Blackwell; 2009
Siewert JR, Stein HJ. Classification of adenocarcinoma of the esophagogastric junction. Br J Surg 1998;
[5].
SC R
85(11): 1457-1459
Malthaner RA, Wong RKS, Spithoff K, et al.: Gastrointestinal Cancer Disease Site Group. Preoperative or postoperative therapy for resectable oesophageal cancer: an updated practice guideline. Clin Oncol (R Coll
[6].
U
Radiol). 2010 May;22(4):250-6
Wong RK, Malthaner RA, Zuraw L, et al.: Combined modality radiotherapy and chemotherapy in nonsurgical
N
management of localized carcinoma of the esophagus: a practice guideline. Int J Radiat Oncol Biol Phys 2003;
[7].
A
55: 930-942
Brouwers M, Kho ME, Browman GP, Cluzeau F, feder G, Fervers B, Hanna S, Makarski J on behalf of the
M
AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. Can Med Assoc J. Dec 2010, 182:E839-842 Ajani JA, D’Amico TA, Almhanna K, et al.: NCCN Clinical Practice Guidelines in Oncology: Esophageal and
ED
[8].
esophagogastric junction cancers. J Natl Compr Canc Netw. 2011 Aug 1;9(8):830-87 Lerut T, Stordeur S, Verleye L, et al.: Update of the national guideline on upper gastrointestinal cancer-
PT
[9].
appendix. Good Clinical Practice (GCP). Brussels: Belgian Health care Knowledge Centre (KCE). 2012. KCE
CC E
Report 179S. D/2012/10.273/35. Available at: https://kce.fgov.be/sites/default/files/atoms/files/KCE_179S_update_upper_gastrointestinal_cancer_appendix _0.pdf. Accessed in October 11, 2017
[10]. GRADE working group Web site. Available at: http://www.gradeworkinggroup.org. Accessed October 11,
A
2017
[11]. Lordick F, Mariette C, Haustermans K, et al.: Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v50-v57 [12]. Jang R, Darling G, Wong RKS. Multimodality approaches for the curative treatment of esophageal cancer. J Natl Compr Canc Netw. 2015 Feb;13(2):229-38 [13]. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement PRISMA-P
13
Group. Syst Rev. 2015; 4(1): 1. Published online 2015 Jan 1. doi: 10.1186/2046-4053-4-1 [14]. Mariette C, Dahan L, Mornex F, et al.: Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol 2014; 32: 2416-2422 [15]. Teoh AY, Chiu PW, Yeung WK, et al.: Long-term survival outcomes after definitive chemoradiation versus surgery in patients with resectable squamous carcinoma of the esophagus: results from a randomized controlled trial. Ann Oncol 2013; 24: 165-171
IP T
[16]. Wang F, Wang YM, He W, et al. Chemoradiotherapy followed by surgery could improve the efficacy of treatments in patients with resectable esophageal carcinoma. Clin Med J (Engl) 2013; 126: 3138-3145
[17]. Kumagai K, Rouvelas I, Tsai JA, et al. Meta-analysis of postoperative morbidity and perioperative mortality
oesophageal junctional cancers. Br J Surg 2014; 101: 321-338
SC R
in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-
[18]. Zheng B, Zheng W, Zhu Y, et al. Role of adjuvant chemoradiotherapy in treatment of resectable esophageal
U
carcinoma: a meta-analysis. Chin Med J 2013; 126: 1178-1182
[19]. Ronellenfitsch U, Schwarzbach M, Hofheinz R, et al. Perioperative chemo(radio)therapy versus primary
N
surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus.
A
Cochrane Database Syst rev 2013: CD008107
M
[20]. Wang DB, Zhang X, Han HL, et al. Neoadjuvant chemoradiotherapy could improve survival outcomes for esophageal carcinoma: a meta-analysis. Dig Dis Sci 2012; 57:3226-3233
ED
[21]. Pottgen C, Stuschke M. Radiotherapy versus surgery within multimodality protocols for esophageal cancermeta-analysis of the randomized trials. Cancer Treat Rev 2012; 38:559-604 [22]. Xu XH, Peng XH, Yu P, et al. Neoadjuvant chemotherapy for resectable esophageal carcinoma: a meta-analysis
PT
of randomized clinical trials. Asian Pac J cancer Prev 2012; 13: 103-110 [23]. Kranzfelder M, Schuster T, Geinitz H et al. Meta-analysis of neoadjuvant treatment modalities and definitive
CC E
non-surgical therapy for oesophageal squamous cell cancer. Br J Surg 2011; 98: 768-783
[24]. Markar SR, Gronnier C, Pasquer A et al. Role of neoadjuvant treatment in clinical T2N0M0 oesophageal cancer: results from a retrospective multi-center European study. Eur J Cancer 2016; 56: 59-68
A
[25]. Nygaard K, Hagen S, Hansen HS, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992; 16: 1104-1109 [26]. Apinop C, Buttisak P, Preecha N. A prospective study of combined therapy in esophageal cancer. Hapatogastroenterology 1994; 41: 391-393 [27]. Le Prise E, Etienne PL, Meunier B, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994; 73: 1779-1784
14
[28]. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462-467 [29]. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001; 19: 305-313 [30]. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. N Engl J Med 1997; 337: 161-167 [31]. Lee JL, Park SI, Kim SB, et al. A single institutional phase III trial of preoperative chemotherapy with
IP T
hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 2004; 15: 947-954
[32]. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery
SC R
for resectable cancer of the oesophagus: a randomized controlled phase III trial. Lancet oncol 2005; 6: 659668
[33]. Natsugoe S, Okumura H, Matsumoto M, et al. Randomized controlled study on preoperative
U
chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer In a single
N
institution. Dis Esophagus 2006; 19: 468-472
[34]. Van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or
A
junctional cancer. N Engl J Med 2012; 366: 2074-2084
M
[35]. Ariga H, Nemoto K, Miyazaki S, 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;
ED
75: 348-356
[36]. Peng L, Xie TP, Han YT, et al. Randomized controlled study on preoperative concurrent chemoradiotherapy
PT
versus surgery alone for esophageal squamous cell carcinoma. Tumor 2008; 28: 620-622 [37]. Fiorica F, Di Bona D, Schepis F, et al. Preoperative radiochemotherapy for oesophageal cancer: a systematic
CC E
review and meta-analysis. Gut 2004; 53: 925-930 [38]. Saeki H, Morita M, Nakashima Y, et al. Neoadjuvant chemoradiotherapy for clinical stage II-III esophageal squamous cell carcinoma. Anticancer Res 2011; 31: 3073-3077
[39]. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil,
A
radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 2008; 26: 1086-1092
[40]. Kaklamanos IG, Walker GR, Ferry K, et al. Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials. Ann Surg Oncol 2003; 10: 754761 [41]. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003; 185; 538-543
15
[42]. Sjoquist KM, Burmeister BH, Smithers BM, eta l. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011; 12: 681-692 [43]. Oppedijk V, van derGaast A, van Lanschot JJ, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol 2014; 32: 385-391 [44]. Shapiro J, van Lanschot JJ, Hulshof MC, van der Gaast A. Effectiveness of neoadjuvant chemoradiotherapy for early-stage esophageal cancer. J Clin Oncol 2015 Jan 20; 33(3): 288-9
IP T
[45]. Czito B, Palta M, Willett C. Results for the FFCD 9901 trial in early-stage esophageal carcinoma: is it really about neoadjuvant therapy? J Clin Oncol 2014; 32: 2398-2400
[46]. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without
SC R
preoperative chemotherapy in oesophageal cancer: a randomized controlled trial. Lancet 2002; 359: 1727-1733 [47]. Wang C, Ding T, Chang L. A randomized clinical study of preoperative chemotherapy for esophageal carcinoma. Zhonghua Zhong Liu Za Zhi 2001; 23: 254-255
U
[48]. Schlag PM. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The
N
Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg 1992; 127: 1446-1450
A
[49]. Maipang T, Vasinanukorn P, Peptichetchian C, et al. Induction chemotherapy in the treatment of patients with
M
carcinoma of the esophagus. J Surg Oncol 1994; 56: 191-197 [50]. Law S, Fok M, Chow S, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell
ED
carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997; 114: 210-217 [51]. Baba M, Natsugoe S, Shimada M, et al. Prospective evaluation of preoperative chemotherapy in resectable
PT
squamous cell carcinoma of the thoracic esophagus. Dis Esophagus 2000; 13: 136-141 [52]. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves
CC E
significantly the long-term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer 2001; 91: 2165-2174
[53]. Allum WH, Stenning Sp, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of
A
surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009; 27: 5062-5067
[54]. Boonstra JJ, Kok TC, Wijnhoven BP, et al. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer 2011; 11: 181 [55]. Kelsen DP, Winter KA, Gunderson LL, et al. 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 2007; 25: 3719-3725
16
[56]. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988; 96: 242-248 [57]. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998; 339: 1979-1984 [58]. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011; 29:
IP T
1715-1721 [59]. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11-20
SC R
[60]. Stahl M, Walz MK, Stuschke M, et a. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009; 27: 851-856
U
[61]. Burmeister BH, Thomas JM, Burmeister EA, et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomized phase II trial. Eur J Cancer
N
2011; 47: 354-360
A
[62]. Leong T, Smithers BM, Haustermans K et al. TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results
M
from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG. Ann Surg Oncol 2017; 24:2252-2258
ED
[63]. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345; 725-730
PT
[64]. Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin
CC E
Oncol 2012; 30: 2327-2333
[65]. Teniere P, Hay JM, Fingerhut A, Fagniez PL. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus As shown by a multicenter controlled trial. French University Association for Surgical Research. Surg Gynecol Obstet 1991; 173: 123-
A
130
[66]. Arnott SJ, Duncan W, Gignoux M, et al. Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal cancer Collaborative Group). Int J Radiat Oncol Biol Phys 1998; 41: 579-583 [67]. Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2010, Issue 1. Art No.: CD002092
17
[68]. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999; 281: 1623-1627 [69]. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002; 20(5): 1167-1174 [70]. Chiu PW, Chan AC, Leung SF, et al. Multicenter prospective randomized trial comparing standard esophagectomy with chemoradiotherapy for treatment of squamous esophageal cancer: early results from the
IP T
Chinese University Research Group for esophageal Cancer (CURE). J Gastrointest Surg 2005; 9: (6): 794-802 [71]. Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and
SC R
cisplatin in patients with esophageal cancer: final results of a randomized, phase 2/3 trial. Lancet Oncol 2014; 15: 305-314
[72]. Merten EV, van Rij C, Tesselaar ME, et al. Definitive concurrent chemoradiotherapy (CRT) with weekly paclitaxel and carboplatin for patients (pts) with irresectable esophageal cancer: a phase II study (abs). J Clin
U
Oncol 2010; 28(suppl): Abs e14508
N
[73]. Ruppert BN, Watkins JM, Shirai K, et al. Cisplatin/paclitaxel as definitive chemoradiotherapy for
A
locoregionally advanced esophageal cancer. Am J Clin Oncol 2010, 33: 346-352 [74]. Wang H, Ryu J, Gandara D, et al. A phase II study of paclitaxel, carboplatin, and radiation with or without
M
surgery for esophageal cancer. J Thorac Oncol 2007; 2: 153-157 [75]. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally
ED
advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005; 23: 2310-2317 [76]. Bedenne L, Michel P, Bouche O, et al. Chemoradiation followed by surgery compared with chemoradiation
PT
alone in squamous cancer of the esophagus. FFCD 9102: J Clin Oncol 2007; 25: 1160-1168 [77]. Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus
CC E
chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010 Aug 28; 376(9742):687-97
[78]. Pravettoni G, Mazzocco K, Gorini A et al. Understanding cognitive processes behind acceptance or refusal of
A
phase I trials. Critical reviews in oncology/hematology 2016; 100: 69-73
[79]. Kondylakis H, Koumakis L, Tsiknakis M et al. Smart recommendation services in support of patient empowerment and personalized medicine. In Multimedia Services in Intelligent Environments. Springer International Publishing 2013; 39-61 [80]. Kondylakis H, Koumakis L, Genitsaridi E et al. IEmS: A collaborative environment for patient empowerment. In Bioinformatics & Bioengineering (BIBE), 2012 IEEE 12th International Conference 2012; 535-540
18
[81]. Hingorani M, Crosby T, Maraveyas A et al. Neoadjuvant Chemoradiotherapy for Resectable Oesophageal and Gastro-oesophageal Junction Cancer – Do we need another randomised trial? Clin Oncol (R Coll Radiol) 2011
A
CC E
PT
ED
M
A
N
U
SC R
IP T
Dec; 23(10):696-705
19
S1040-8428(17)30325-6 https://doi.org/10.1016/j.critrevonc.2018.10.002 ONCH 2632
To appear in:
Critical Reviews in Oncology/Hematology
Received date: Revised date: Accepted date:
29-6-2017 22-9-2018 9-10-2018
Please cite this article as: Chiappa A, Andreoni B, Dionigi R, Spaggiari L, Foschi D, Polvani G, Orecchia R, Fazio N, Pravettoni G, Cossu ML, Galetta D, Venturino M, Ferrari C, Macone L, Crosta C, Bonanni B, Biffi R, A rationale multidisciplinary approach for treatment of esophageal and gastroesophageal junction cancer: accurate review of management and perspectives, Critical Reviews in Oncology / Hematology (2018), https://doi.org/10.1016/j.critrevonc.2018.10.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A rationale multidisciplinary approach for treatment of esophageal and gastroesophageal junction cancer: accurate review of management and perspectives
IP T
Running title: Treatment of esophageal and gastroesophageal junction cancer in the era of multidisciplinary approach
SC R
Antonio Chiappa1, MD, F.A.C.S., Bruno Andreoni2, MD, Renzo Dionigi3, MD, F.A.C.S., F.R.C.S. (Hon Ed), Lorenzo Spaggiari4, MD, Diego Foschi5, MD, Gianluca Polvani6, MD, Roberto Orecchia7, MD, Nicola Fazio8, MD, Gabriella Pravettoni9, MD, Maria Laura Cossu10, MD, Domenico Galetta4, MD, Marco Venturino11, MD, Carlo Ferrari1, MD, Lorenzo Macone2, 1, Cristiano Crosta12, MD, Bernardo Bonanni13 MD, Roberto Biffi14, MD
Unit of Innovative Surgical Techniques-University of Milano and European Institute of Oncology-ITALY Unit of Innovative Techniques in Surgery European Institute of Oncology University of Milan – ITALY
2
University of Milan Milan – ITALY
3
Department of Surgery University of Insubria Varese – ITALY
4
Department of Thoracic Surgery European Institute of Oncology University of Milan – ITALY
5
Department of Surgery “Luigi Sacco” Hospital University of Milan – ITALY
6
Cardiothoracic Surgery “Monzino” Cardiologic Institute University of Milan – ITALY
7
Department of Radiotherapy European Institute of Oncology University of Milan – ITALY
8
Unit of Medical Oncology European Institute of Oncology Milan – ITALY
10
N A M ED
PT
Unit of Psycho-Oncology European Institute of Oncology University of Milan – ITALY Division of General Surgery II University Hospital of Sassari; Department of clinical and Trial Medicine University of Sassari – ITALY Division of Anaesthesiology European Institute of Oncology Milan – ITALY
A
11
CC E
9
U
1
12
Division of Endoscopy European Institute of Oncology Milan-ITALY
13
Division of Cancer Prevention European Institute of Oncology Milan – ITALY
14
Division of Digestive Tract Surgery European Institute of oncology Milan – ITALY
1
Corresponding Author and address: Antonio Chiappa, MD, F.A.C.S. Dept of General Surgery-University of Milano European Institute of Oncology Via G. Ripamonti, 435 20141 – MILANO – ITALY Email: [email protected] Email: [email protected]
Abstract:
PT
ED
M
A
N
U
SC R
IP T
Graphical abstract
Cancer of the esophagus and of gastroesophageal junction can be cured, even if with lacking cure rate. Different
CC E
approaches have been developed, mostly when carcinoma has loco-regional pattern. Multimodality therapy showed a survival rate superior than 10% if compared to a single approach. This is a systematic review, carried to assess the following matters: Which therapeutic opportunities are available? Who could benefit of them? Which adverse reactions could possibly verify? How can physicians definitely choose the proper strategy? Which is the role of surgery? We
A
mean to give either General Practitioner or specialists clear and efficient updates about current treatment of this tumour, starting from physical examination. Four eminent guidelines were consulted for our study: Cancer Care Ontario’s Program in Evidence-Based Care, NCCN, Belgian Health Care Knowledge Centre and Esmo.
Abbreviations used in the text: NCCN: National Comprehensive cancer Network; SCC: Squamous Cell carcinoma; UICC: Union for International Cancer Control; EGJ: Esophagogastric junction; CCO: Cancer Care Ontario Program; OS: Overall Survival; CRT: Chemo-radiotherapy; CT: chemotherapy; RT: radiotherapy; 5-FU: 5-Fluorouracil.
2
1
Introduction The Globocan 2012 asserted that cancer of the esophagus is the eighth most common cancer worldwide, sixth
for mortality, with approximately 496,000 cases in 2015. Less developed countries are most likely to develop this disease (80%), although incidence is truly variable worldwide [1]. Despite the fact that the survival rate has been slowly increasing in the U.S.A. by around 0.7% per year (2002-2012), perhaps after the adhesion to multimodality techniques for treatment and improved supportive care, the worldwide survival rate has not been superior to 18.8% at 5 years yet [2]. Nevertheless, the fundamental principle to treat this cancer remains a “tailored” therapy, based on comorbidities. The two predominant histological subtypes of esophageal cancer are adenocarcinoma and squamous cell
IP T
carcinoma (SCC). The UICC-TNM stages provide useful prognostic parameters, which differ slightly between histological subtypes [3]. As, historically, squamous cell carcinoma (SCC) and adenocarcinoma are believed to have similar clinical progression, they are assumed as a single entity. Recent Authors assert that cytology, histology and therapy
SC R
efficacy should be the keystones of management. Furthermore, local lymphatic involvement seems to have an important role in surgical and radiotherapy strategy planning.
The incidence of esophageal cancer does not seem to decrease (16,940 new cases estimated [2]), probably due to increasing incidence of adenocarcinoma of the lower third of the esophagus and of the esophagogastric junction (EGJ).
U
Cancers of EGJ are defined as those that arise within 5 centimeters of the anatomical cardia. Siewert type I EGJ tumours
N
has their centre located between 5 and 1 cm proximally to anatomical cardia. They usually arise from an area of Barrett’s metaplasia in the lower esophagus and infiltrate the EGJ distally; Siewert type II tumours arise at the true cardia
A
immediately at the EGJ, and type III tumours originate in the subcardial area (2 to 5 cm distally) and infiltrate the EGJ
Siewert Classification
ED
Type 1
M
proximally [4, Figure 1].
Anatomical site of tumour centre
5 cm – 1 cm proximally to anatomical cardia Cardia (“pure” junctional tumour)
Type 3
2-5 cm distally to anatomical cardia
PT
Type 2
Figure 1. The Siewert classification: EGJ tumours are classified in relation to their anatomical site.
CC E
The clinical management of malignancies of the gastroesophageal junction (EGJ) is currently one of the most challenging scientific issues. To classify junctional tumours, we refer to the 7th edition of the Union for International Cancer Control (UICC) TNM staging system. In this study, tumours with an epicentre within 5 centimeters of the EGJ and extend into the esophagus are classified and staged using the esophageal system [3].
A
The present study deals with some important issues, critical in clinical decision-making, from examination to treatment of patients: -
Which therapeutic opportunities are available?
-
Who could benefit of them?
-
Which adverse reactions could possibly verify?
-
How can physicians definitely choose the proper strategy?
-
Which is the role of surgery?
3
These questions should find their own answer in this article, through the studies that we mean to mention. Our aim is to clarify the attitude a multidisciplinary board should have in order to treat esophageal cancer with curative intent.
2
Methods We discuss data from available clinical trials, meta-analyses and guidelines in the non-surgical treatment of
resectable esophageal and EGJ cancer. The electronic database PubMed was searched (since August 2015) and we selected several trials (randomized, non-randomized, prospective, multicentred, etc.), but only randomized trials and
IP T
systematic reviews were used to provide evidence-base conclusions. Four guidelines (since 2012) has been used: the Cancer care Ontario’s Program in Evidence-Based Care (CCO PEBC) has a good AGREE score [5, 6, 7]. The National Comprehensive Cancer Network (NCCN) recruited appreciable and reliable sources [8]. The Belgian Health Care
SC R
Knowledge Centre (KCE reports 179A) used the GRADE methodology and nomenclature [9, 10]. The new 2016 ESMO clinical practice guidelines represent the latest management indications available and supply an efficient and current summary to approach this disease, provided by a board of eminent and expert researchers [11]. Recommendations from the previously mentioned guidelines were evaluated. A really well conducted 2015 review by Jang et al. was considered for our study [12]. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for
U
systematic reviews were used for our study [13].
N
An overview of the amount and the years of the studies we have consulted is reported in Table 1. They are
Guidelines
4
2003 - 2016
Trials
51
1988 - 2017
21
1988 - 2017
Meta-analyses
10
1998 - 2014
Reviews
6
2004 - 2016
Randomized
3
CC E
Table 1. Studies consulted.
PT
-
M
Years
ED
N°
A
mentioned all over in the text.
Results
Non surgical techniques for the treatment of esophageal cancer
A
As surgery is the common treatment of choice in local disease, several issues arise when discussing advanced
disease. While adjuvant therapy has a consolidated role in treating cancer, neoadjuvant therapy has recently gained consideration in clinical practice. There are many trials, meta-analyses and systematic reviews (mentioned by CCO PEBC guidelines too). Two additional randomized trials [14, 15], and 7 meta-analyses and systematic reviews were published after CCO PEBC guidelines [16-22]. ESMO guidelines mention several and meta-analyses that we used for our study. Additionally, ESMO team included a meta-analysis by Kranzfelder et al. [23] and a retrospective multi-centre study carried by Markar et al. [24] both assessing the role of neoadjuvant therapy. All trials, meta-analyses and reviews are mentioned in our “References” section.
4
Several attempts to improve outcomes arouse, including neoadjuvant CRT, peroperative chemotherapy, exclusive-definitive CRT, and adjuvant CRT. Concerning the current literature, none of them is accompanied by strong evidences of better outcomes neither in the 5-year survival, nor in the R0 resection. The techniques and the related results in clinical trials are the following. Preoperative CRT and perioperative chemotherapy Multiple strategies including preoperative CRT, peroperative chemotherapy alone, exclusive CRT, and adjuvant
IP T
CRT in advanced esophageal cancer, symbolise the effort to improve outcomes in advanced cancer of the esophagus.
The assessment of preoperative CRT originates from a total of several randomized trials [14, 23-36], while the
SC R
two most recent voices are the critical CROSS trial (2012) [32] and FFCD 9901 trial (2014) [14].
A 2004 review [37] including different meta-analyses stated that trials analyzing this strategy were quite equivalent. The main result was a survival improving at 3 years [38-41]. A meta-analysis included results from the CROSS trial and confirmed the survival benefit of neoadjuvant CRT over surgery alone (hazard ratio (HR), 0.78; 95% CI, 0.70-
U
0.88; p<0.0001), estimated as 8.7% at 2 years [42].
N
The CROSS trial [34] consisted of 366 patients with either adenocarcinomas or EGJ cancers and was the widest single-study trial of preoperative CRT versus surgery alone. Patients were randomized in two groups: the first one
A
received 41.4 Gy of radiotherapy (duration: 5 weeks) with simultaneous weekly carboplatin and paclitaxel (50 mg/m2)
M
followed by surgery; the second group had only surgery. Macro- and microscopic pathologic complete response was completed in 29% of treated patients. Eventually, the preoperative CRT group had better cancer specific survival. (HR of 0.657, 95% CI, 0.495-0.871; p=0.003). The overall cancer specific survival advantage at 5 years was approximately 13%.
ED
Low rates of loco-regional recurrences and metastases were reported [43]. FFCD 9901 randomized trial enrolled patients with early-stage (stages I and II) esophageal cancer with
PT
histological evidence. Two arms were set: one composed by patients undergone CRT (45 Gy in 25 fractions for 5 weeks with 2 cycles of simultaneous chemotherapy with 800 mg/m2 of fluorouracil and 75 mg/m2 of cisplatin) followed by surgery; another one who received surgery only. Overall survival curves for the 2 arms resulted in a crossing at 3 to 4
CC E
years. The combined arm showed a higher survival rate after 4 years. As also Shapiro and colleagues [44] observe, the higher postoperative complications rate in combined arm (11.1% vs 3.4%, p=0.02) could be the effect of a low case volume in the centres enrolled in this trial (195 patients in 30 centres in 9 years). Czito and colleagues [45], as Shapiro,
A
suggest that a possible underlying cause of this rate could be the quality of chemoradiotherapy regimens too. However, integrating these data and applying them to eligible patients, combined therapy seems to provide a
survival advantage, resulting a suitable treatment strategy, mostly in II stage cancer. CROSS trial remains the leading reference, concerning its methods and results. Neoadjuvant chemotherapy
5
Data concerning the trial mentioned so far suggested that the proportion of patients completing the postoperativeadjuvant regimen is limited, with a consistent part of the benefit from the perioperative treatment attributable to the preoperative-neoadjuvant component. Some authors [19, 42] recently realised a meta-analysis of trials concerning the neoadjuvant treatment of esophageal cancer and revealed an improved survival, with an HR of 0.87 (95% CI, 0.79-0.96; p=0.005). Preoperative chemotherapy with surgery was studied in several randomized trials [25, 46-55]. Yet, three other trials focused on the benefit of perioperative chemotherapy [56-58].
IP T
This regimen of treatment has been often supported in various studies dealing with perioperative esophagus cancer chemotherapy. We have some data about 36 patients in a study by Roth and coworkers, but, although the randomization, the sample was too small to produce reliable recommendations [56]. Regarding this, two important voices
SC R
were Kelsen and Ychou. Kelsen led a US Intergroup trial (RTOG 8911, US Intergroup 113) in 2007 with 467 cases [55, 57]. Ychou carried a trial in 2011 in which 224 patients participated [54]. The design of these two studies was similar (regimen based on cisplatin plus fluorouracil). Nevertheless, the results were different: only the trial of Ychou had positive results. This disproportion could be related to the higher presence of advanced cancers in the US trial (10% weight loss at diagnosis was about 23% and R0 resection was 60%). It is not unusual that a heterogeneous recruitment may cause
U
such different data.
N
In contrast, Cunningham and his trial, dealing with the single perioperative chemotherapy for gastric cancer [59],
A
including lower esophagus and EGJ adenocarcinomas (25%), was important in changing clinical practice. A significant
the sample was wide enough.
ED
Neoadjuvant chemoradiotherapy, is it possible?
M
5 years overall survival benefit with perioperative chemotherapy versus surgery alone was reported (36% vs 23%) and
Another issue remains open: why and when neoadjuvant CRT versus neoadjuvant chemotherapy alone in adenocarcinomas? Unfortunately, two randomized trials attempting to clarify this debate failed to provide a proper answer
PT
[60, 61].
Stahl and coworkers reported a single-phase III trial (known as POET trial) comparing these strategies [60]. It
CC E
included 126 patients with equal proportion of Sievert I and II/III adenocarcinoma of the EGJ. The study was early closed because of poor accrual and results did not gain statistical significance. However, the study evidenced a 3 years absolute survival rate that supported preoperative CRT (47.7% vs 27.7%). Burmeister et al. in his study [61] reported no difference in survival between the two techniques, but remarked
A
an improvement in margin involvement with the addition of radiotherapy. The trial was conducted on 75 patients with esophagus/EGJ adenocarcinomas smaller than 2 cm. The choice of the adequate strategy must be guided by clinical experience and the presence of comorbidities. The extent of the tumour, especially in the cranio-caudal direction, may expose a significant portion of lungs and heart to massive doses of radiation. Preoperative chemotherapy without radiotherapy may be preferred when nodal involvement exceeds the target volume or in presence of significant primary tumour length. In the CROSS trial were included only patients with a cancer extension (either cranio-caudally or laterally) within 8 cm [34]. nCRT seems suitable to patients who have a major lateral involvement by tumour. Assuming R0 resection and histopathological complete response
6
evidence as intermediate outcome, nCRT results in an advantage for these patients. This could highlight the importance of the radiotherapeutic component in down-staging the cancer. For gastro-esophageal tumours invading the gastric cavity, a higher pattern of nodal spread has been evidenced, as for gastric cancer. The usual radiotherapy settings employed in the current trials are designed to include peri-esophageal nodes. Perhaps radiotherapy might be the discriminating factor, which could enhance, at the same time, the treatment of the lesion itself and of the nodes too. The debate about toxicity is, therefore, worthy. Toxicity is an intermediate end-point in TOPGEAR trial [62] (see below in “Toxicity”). Concerning some authors [63, 64], postoperative CRT is not a recommended option for patients with esophageal cancers that are above the EGJ, but only for those with a clear EGJ cancer.
IP T
Although they are not properly recent data, reliable evidences carried by Teniere and Arnott [65, 66] demonstrate a lack of survival benefit with radiotherapy alone (either preoperative or postoperative). On the other hand, there is lack
SC R
of data to choose exclusively adjuvant chemotherapy. Definitive CRT versus CRT with or without surgery
Two important resources in treating this cancer are definitive CRT and combined modality with surgery. The first one is usually reserved to those with several comorbidities or who express a clear refusal of surgery. Squamocellular
U
cancer is becoming more in more unresectable (although further studies are needed to give it significative evidence). By contrast, surgeons and geriatric specialists are not considering advanced age as a contraindication anymore. Actually, in
N
clinical practice, we witness even elderly patients undergoing esophagectomy.
A
Wong realised in 2006 a cochrane review (updated and withdrawn in 2010) in which he stated that, when a non-
M
operative approach is chosen, concomitant RCT is better than RT alone for patients with localized esophageal cancer but with significant toxicities [67]. However, if physical status is not particularly compromised, CRT may be applied as well.
ED
Definitive CRT was first evaluated in the RTOG 85-01 study [68] on 129 patients with localized (T1-3N0-1M0) esophageal SCC or adenocarcinoma. The study demonstrated an improved 5-year OS of 26% in patients randomized to four cycles of cisplatin 75 mg/m2 (day 1) and 5-FU 1000 mg/m2/day (days 1-4) with radiotherapy (50 Gy) compared with
PT
0% in those randomized to radiotherapy (64 Gy) alone. In the subsequent nonrandomized part of this study, a modest 5year OS of 14% was reported in the 73 patients assigned to CRT. Persistence of disease was most common in patients treated with radiotherapy alone (37% vs 25-28% with CRT). No further deaths due to esophageal cancer were observed
CC E
after 5 years. They asserted found the 8 years OS was 22% of the combined randomized group, suggesting that a proportion of patients can be really cured with CRT alone, not merely palliated for a longer time. In the attempt to reduce the persistence of local disease and reduce rates of loco-regional failure, the subsequent
A
RTOG 94-05 trial, investigated intensification of radiation therapy to 64.8 Gy with the same chemotherapy regimen used in RTOG 85-01, compared with chemotherapy plus the standard radiation therapy (50.4 Gy) [69]. This randomized phase III trial enrolled 236 patients with localized (T1-4 N0-1 M0) SCC or adenocarcinoma, of whom over 80% had SCC. No benefit in 2-year survival was demonstrated (2-year OS 31% vs 40% with standard CRT) and similar local persistence and loco-regional failure rates were observed in both arms. By contrast, treatment-related mortality was greater in patients randomized to the higher radiotherapy dose, showing a quite narrow therapeutic index. It is necessary, therefore, that a proper balance is assessed between efficacy and toxicity.
7
The relative benefit of definitive CRT over a purely surgical approach was evaluated in a small study including 80 patients with SCC who were randomized to definitive CRT with cisplatin 60 mg/m2 (days 1 and 22), infused fluorouracil 200 mg/m2/day (days 1-42) with radiotherapy (50-60 Gy) or surgery alone. No significant difference in median disease-free survival (20 vs 24 months with surgery) or 2-year OS (58.3% vs 54.5% with surgery) was reported at a median follow-up of 16.9 months [70]. However, the perioperative mortality rate in the surgery group was 6.8%. Six patients in the CRT arm underwent salvage surgery for persistent or recurrent disease, in which the perioperative mortality was 16.7%. However, surgery alone would not be considered a standard approach, due to complications; therefore a comparison of definitive CRT with neo-adjuvant CRT was made.
IP T
Nowadays, cisplatin and fluorouracil are considered the cornerstone. Conray et al. compared fluorouracil plus cisplatin and radiotherapy with FOLFOX regimen and radiotherapy, finding comparable survival rates [71]. Side reactions were slightly different. Merten et al., by contrast, focused on a carboplatin and paclitaxel plus a 50.4 Gy radiotherapy approach in locally unresectable patients [72]. That was judged as a tolerable regimen, leading to durable loco-regional
SC R
control and palliation in nearly half of patients, although a little amount of side effects occurred. 2 and 3-year survival were, respectively, 32% and 16%. Ruppert and Wang also experimented this approach [73, 74]. Definitive CRT versus surgery alone
U
We have only non-statistically significant data about CRT alone (definitive) versus surgery alone. In the study
N
carried by Teoh, 5-year OS was 50% with definitive CRT (vs 29% with surgery alone) and similar results were seen in
A
disease-free survivals [15].
M
Neoadjuvant CRT versus definitive CRT
Trials comparing preoperative CRT followed by surgery versus definitive CRT have been done mostly with SCC
ED
[75 ,76].
The first one by Stahl et al. used a regimen of induction CT plus CRT plus surgery plus RT (total dose 65 Gy) [75]. In the second trial by Badenne et al. (89% of SCC) the responsive patients after induction CT were randomized in
PT
two groups: one had further CRT and the other one received surgery [76]. These 2 trials had equivalent design. Results are the following: Stahl had an OS at 2 years of 33.6% for preoperative CRT and 39.8% for CRT alone; local control rate at 2 years was better in surgery arm (64.3% vs 40.7%). Baden had an OS at 2 years of 39.9% for preoperative CRT and
CC E
35.4% for CRT alone; local control rate at 2 years was still better in surgery arm (66.7% vs 57.0%). Surgery had, however, more complications.
There is need of further analyses, as all these studies used different regimens from the commonly used.
A
Salvage surgery
It is not uncommon, in oncology, to treat too painful discomforts or terminal conditions with surgery. For
instance, in lower gastrointestinal tumours or in pelvic diseases spread to the entire cavity, surgeons usually perform an ileostomy in order to canalize patients or to avoid occlusions. In esophageal cancer, this may be referred to dysphagia or airways involvement. In his study, Ariga and colleagues focused on the role of salvage surgery in a group of selected patients with thoracic esophageal squamocellular cancer [35]. 5-year OS was 75.7% in the CRT-alone arm and 50.9% in surgery arm. Of the first group, 25.5% had salvage esophagectomy. CRT was, thus, comparable or superior to salvage surgery.
8
Unfortunately, we have data only for patients with SCC, not for adenocarcinomas. The correct strategy to evaluate responses require further investigation, with regular and strict intervals of follow-up, although CRT alone seems to be a suitable approach in these cases. Toxicity In perioperative treatment, gastrointestinal and hematologic toxicities predominate. Possible gastrointestinal side effects are: nausea, vomiting, dysphagia, esophagitis, anorexia, diarrhea, etc. As for hematopoietic system: neutropenia, anemia, leukopenia, thrombocytopenia, etc. There are some possible complications during or after surgical operation:
IP T
anastomotic leak, intra-abdominal sepsis, wound infection, chest infection, respiratory failure, cardiac ischemia, etc. Toxicity of this technique is examined in the TOPGEAR trial that means to be a useful to guide clinical practice (Clinical Trials.gov identifier: NCT01924819). The interim analysis was recently published [62], demonstrating that
SC R
preoperative chemoradiotherapy is a safe procedure without increase in treatment toxicity. Further data about survival improving are expected at the end of the trial. That is one of the most pivotal trials dealing with this disease, mostly due to its relevant sample. These factors should be considered when selecting between these two modalities in the management of adenocarcinomas of the esophagus and EGJ. The rationale is to use chemo-radiotherapy in neoadjuvant setting,
U
switching to chemotherapy alone if adverse events (i.e. toxicities) develop.
N
On-going trials and the future
TOPGEAR trial has been discussed above. Several other trials dealing with this issue are being carried. We
Neoadjuvant Chemotherapy Versus Radiochemotherapy for Cancer of the Esophagus or Cardia
M
A
mention the most relevant to our study.
(NeoRes) (ClinicalTrials.gov Identifier: NCT01362127)
ED
This is an active non-recruiting trial, conducted by Nilsson et al. (Karolinska University Hospital) which enrolled 180 patients. The outcomes are, firstly, to evaluate wheter nRCT gives higher complete histological response after resection (14-16 weeks after therapy) than CT alone, secondly, to assess
PT
safety profile. The estimated study completion date is June 2018. Preoperative Concurrent Chemoradiotherapy for Locally Advanced Gastroesophageal Junction or Upper Gastric Adenocarcinoma (ClinicalTrials.gov Identifier: NCT02193594)
CC E
This study is still recruiting (214 patients enrolled within the period January 2014 – September 2017). The corresponding researcher is Jiafu Ji and it is carried mostly in Beijing Cancer Hospital. Primary outcome is therefore 3-year survival time and recurrence free survival. Other outcomes include complications rate, pathological responses, etc. The estimated study completion date is May 2020.
A
Perioperative Chemotherapy Compared To Neoadjuvant Chemoradiation in Patients With Adenocarcinoma of the Esophagus (ESOPEC) (ClinicalTrials.gov Identifier: NCT02509286) This study is still recruiting (438 patients enrolled within the period January 2016 - October 2017). The responsible researcher is Prof. Hoeppner and the study is multi-centred, with main setting in Freiburg University Hospital. Outcomes are, firstly, the overall survival; secondly, progression free survival time, failures, recurrence free survival time, quality of life, etc. The study will end in June 2023.
PDL-1 Targeting in Resectable Oesophageal Cancer (PERFECT) (ClinicalTrials.gov Identifier: NCT03087864)
9
This study is still recruiting (40 patients enrolled within the period January 2017 – March 2017). The corresponding author is van Laarhoven (Academisch Medisch Centrum, Universiteit van Amsterdam). Although the limited sample, this study has an ambitious purpose, i.e. to assess the role of target therapy combined to CRT in preoperative phase. Other outcomes concern safety, toxicity, etc. The study is estimated to finish by 2019. Of course we are all waiting for these studies to complete, in order to have further data, which could eventually define the role of nCRT in clinical practice. Despite the feasibility of target-therapy trials is not easy (mostly due to few and compromised patients enrolled), we look at them with confidence. All these data would be really
4
IP T
useful in strengthen esophageal cancer management. Recommendations
SC R
The Ontario panel recommended preoperative CRT with platinum based CT for resectable esophageal cancer. Preoperative platinum based CT alone may be an alternative. These guidelines suggest that for SCC with too high clinical risk, the non-surgical and conservative method is preferable, on the basis of current data [5, 6].
NCCN panel guidelines affirm that patients with localized esophago-gastric cancer benefit from combined
U
modality therapy. Multidisciplinary approach remains a cornerstone, with regular meetings to facilitate decisions, collegial review of data and the need for a special board that could discuss the case thoroughly. According to the
N
guidelines, CRT alone is indicated for T4b (non-resectable) tumours in good clinical status and for resectable tumours
A
(T1bN+, T2-4aN0-N+) in non-clinically stable patients. Medically fit patients with resectable tumours (T1bN+, T2-4aN0N+) should have CRT alone if cervical SCC esophageal cancer is present or for adenocarcinoma cases which refuse
M
surgery [8].
The Belgian guidelines reiterate the importance of multidisciplinary discussion. Neoadjuvant CRT is the
ED
treatment of choice for locally advanced esophageal tumour, with the board consensus. An adjuvant treatment is not habitually recommended. Definitive exclusive CRT should be considered in cases of locally advanced esophageal cancer,
PT
if the tumour is unresectable or the patient is not fit for surgery. No matter which histology belongs to the tumour [9]. The ESMO guidelines state that surgery remains the treatment of choice in limited disease and that nCRT does not improve R0 resection rate (II, B recommendation). If patients are unable or unwilling to receive surgery, then,
CC E
combined CRT is superior to RT alone (II, A recommendation). For locally advanced disease (T3-4, N1-3, M0): adenocarcinomas (considered like gastric tumours) should receive perioperative CT or preoperative CRT (I, A recommendation); SCC should receive nCRT with planned surgery or definitive CRT with close surveillance and salvage surgery for local tumour persistence or progression (II, B recommendation). Metastatic disease should be addressed to
A
palliative treatment [11].
An integrated approach of the above-mentioned guidelines is mandatory. The gist is that resectable tumours
should however undergo surgery, although CRT alone is sometimes a clinical choice. Neoadjuvant CRT is considered the goal; however, selective use of perioperative CT for adenocarcinomas is indicated when RT use is expected to be associated with increased toxicities.
5
Conclusions
10
Based on the current reported data from randomized controlled clinical trials and meta-analyses, definitive concurrent CRT using cisplatin and 5-FU is a useful treatment strategy in SCC of the esophagus, with surgery reserved as a salvage procedure in patients with persistent disease or for those who relapse. However, neoadjuvant CRT followed by surgery remains a valid option, especially for cases at lower surgical risk with an absence of several medical comorbidities, for either SCC or adenocarcinomas. Preoperative platinum-based chemotherapy plus radiotherapy is the preferred modality for the management of surgically resectable loco-regional esophageal cancer. Avoiding RT is still a
ED
M
A
N
U
SC R
IP T
valid choice.
A
CC E
PT
Figure 2. Algorithm for the treatment of local/locoregional resectable thoracic esophageal cancer. EUS, endoscopic ultrasound; FDG-PET, fluorodeoxyglucose-positron emission tomography; MS-CT, multislice-computed tomography; cTNM, clinical tumour, node, metastases classification according to AJCC/ UICC; CRT, chemoradiotherapy; OS, overall survival. 1 Criteria for endoscopic instead of surgical resection are specified in the text. 2 For patients unable or unwilling to undergo surgery, combined CRT is superior to radiotherapy alone. 3 Evidence suggests that neoadjuvant CRT followed by surgery and definitive CRT are equally effective with regard to overall survival. Oesophageal surgery should be carried out in experienced (high volume) centres only. For patients not willing to undergo oesophageal surgery or who are medically unfit for major surgery, definitive chemoradiotherapy should be preferred. Even many experienced centres prefer definitive CRT for oesophageal tumours with a very proximal/cervical location. 4 Sufficient evidence supports the use of perioperative chemotherapy as well as neoadjuvant CRT. Both standards can be recommended with an equal level of evidence/grade of recommendation [I, A]. Several ongoing studies in Europe are comparing both modalities. Inclusion of patients in one of these studies is encouraged. Some centres prefer neoadjuvant CRT for tumours of the oesophagus and AEG type I or II according to the Siewert’s classification, while they use perioperative chemotherapy for AEG type III or II, but this is only a pragmatic solution not currently supported by scientific evidence. 5 This is optional in the case of incomplete response to CRT or local relapse. This should be carried out only in selected patients and experienced centres. Lordick F et al. for the 2016 ESMO Clinical Practice Guidelines [11] elaborated the image. With curtesy of Oxford University Press, order n°: 4210960780868.
The treatment of breast, colon, and lung cancers, as well as hematological malignancies, has successfully made the transition towards personalised medicine by the incorporation of targeted agents for molecular selected patients into routine treatment strategies. The ToGA trial [77] has demonstrated that this is also possible in esophagogastric cancer, although further improvements in survival remain urgently needed. By designing studies with translational correlates, using molecular selection for new-targeted agents and including all willing and eligible patients in these trials, the effects
11
of targeted therapy can be evaluated in a rigorous and significant way in esophageal and EGJ cancers. HER2 receptor is, nowadays, the only target thoroughly studied for this cancer, because it is often associated to gastric cancer. The new development of personalised medicine, however, sheds new light on the role of psychological aspects on clinical outcomes, which are better in patients who are involved in the decision making process [78]. To maximise the effect of therapies, hence, a clinician must not only consider non-clinical aspects that can affect choices, but also the importance to optimise patient empowerment for improving adherence and treatment outcomes [79, 80]. At the moment, as we also can notice with a comparison with other eminent reviewers, innovation is that “there is no innovation” in treating esophageal and EGJ cancer. Of course, we are all waiting for results from above-mentioned
IP T
trials, although targeted and molecular therapy, in a reasonable point of view, will have future supremacy. In 2011, Hingorani et al. showed uncertainty about several different trials arising to deal with this disease, mostly due to contrasting data and, perhaps, non-standardized designs [81]. In that moment, they highlighted the necessity of direct comparison between the accredited therapies. We have remarked enough in this article the current results concerning this disease, and
SC R
we think that current on-going trials are following the right path.
As for as we are concerned, the algorithm [Figure 2] published with last ESMO guidelines [11] is, nowadays, the most useful tool for the management of esophageal cancer, applicable by GP during regular examination, up to the
N
U
specialists in the hospital.
A
Statements and disclosures
M
All the phases of the work have been carried on with the approval of the ethic committee and under the edge of a written consensus to use clinical and biomedical data for scientific purposes, signed by patients
ED
during pre-hospitalization visit.
All Authors have taken part to all stages of this work, design, execution, analysis.
PT
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
A
CC E
There is no financial interest neither any conflict of interests in the whole work
12
References [1].
Globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed October 11, 2017
[2].
Surveillance, Epidemiology, and EndResults Program. SEER Stat fact Sheets: esophageal cancer. Available at: http://seer.cancer.gov/statfacts/html/esoph.html. Accessed October 11, 2017
[3].
Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM classification of malignant tumors. 7 th edition. Oxford,
[4].
IP T
England: Wiley-Blackwell; 2009
Siewert JR, Stein HJ. Classification of adenocarcinoma of the esophagogastric junction. Br J Surg 1998;
[5].
SC R
85(11): 1457-1459
Malthaner RA, Wong RKS, Spithoff K, et al.: Gastrointestinal Cancer Disease Site Group. Preoperative or postoperative therapy for resectable oesophageal cancer: an updated practice guideline. Clin Oncol (R Coll
[6].
U
Radiol). 2010 May;22(4):250-6
Wong RK, Malthaner RA, Zuraw L, et al.: Combined modality radiotherapy and chemotherapy in nonsurgical
N
management of localized carcinoma of the esophagus: a practice guideline. Int J Radiat Oncol Biol Phys 2003;
[7].
A
55: 930-942
Brouwers M, Kho ME, Browman GP, Cluzeau F, feder G, Fervers B, Hanna S, Makarski J on behalf of the
M
AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. Can Med Assoc J. Dec 2010, 182:E839-842 Ajani JA, D’Amico TA, Almhanna K, et al.: NCCN Clinical Practice Guidelines in Oncology: Esophageal and
ED
[8].
esophagogastric junction cancers. J Natl Compr Canc Netw. 2011 Aug 1;9(8):830-87 Lerut T, Stordeur S, Verleye L, et al.: Update of the national guideline on upper gastrointestinal cancer-
PT
[9].
appendix. Good Clinical Practice (GCP). Brussels: Belgian Health care Knowledge Centre (KCE). 2012. KCE
CC E
Report 179S. D/2012/10.273/35. Available at: https://kce.fgov.be/sites/default/files/atoms/files/KCE_179S_update_upper_gastrointestinal_cancer_appendix _0.pdf. Accessed in October 11, 2017
[10]. GRADE working group Web site. Available at: http://www.gradeworkinggroup.org. Accessed October 11,
A
2017
[11]. Lordick F, Mariette C, Haustermans K, et al.: Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v50-v57 [12]. Jang R, Darling G, Wong RKS. Multimodality approaches for the curative treatment of esophageal cancer. J Natl Compr Canc Netw. 2015 Feb;13(2):229-38 [13]. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement PRISMA-P
13
Group. Syst Rev. 2015; 4(1): 1. Published online 2015 Jan 1. doi: 10.1186/2046-4053-4-1 [14]. Mariette C, Dahan L, Mornex F, et al.: Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol 2014; 32: 2416-2422 [15]. Teoh AY, Chiu PW, Yeung WK, et al.: Long-term survival outcomes after definitive chemoradiation versus surgery in patients with resectable squamous carcinoma of the esophagus: results from a randomized controlled trial. Ann Oncol 2013; 24: 165-171
IP T
[16]. Wang F, Wang YM, He W, et al. Chemoradiotherapy followed by surgery could improve the efficacy of treatments in patients with resectable esophageal carcinoma. Clin Med J (Engl) 2013; 126: 3138-3145
[17]. Kumagai K, Rouvelas I, Tsai JA, et al. Meta-analysis of postoperative morbidity and perioperative mortality
oesophageal junctional cancers. Br J Surg 2014; 101: 321-338
SC R
in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-
[18]. Zheng B, Zheng W, Zhu Y, et al. Role of adjuvant chemoradiotherapy in treatment of resectable esophageal
U
carcinoma: a meta-analysis. Chin Med J 2013; 126: 1178-1182
[19]. Ronellenfitsch U, Schwarzbach M, Hofheinz R, et al. Perioperative chemo(radio)therapy versus primary
N
surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus.
A
Cochrane Database Syst rev 2013: CD008107
M
[20]. Wang DB, Zhang X, Han HL, et al. Neoadjuvant chemoradiotherapy could improve survival outcomes for esophageal carcinoma: a meta-analysis. Dig Dis Sci 2012; 57:3226-3233
ED
[21]. Pottgen C, Stuschke M. Radiotherapy versus surgery within multimodality protocols for esophageal cancermeta-analysis of the randomized trials. Cancer Treat Rev 2012; 38:559-604 [22]. Xu XH, Peng XH, Yu P, et al. Neoadjuvant chemotherapy for resectable esophageal carcinoma: a meta-analysis
PT
of randomized clinical trials. Asian Pac J cancer Prev 2012; 13: 103-110 [23]. Kranzfelder M, Schuster T, Geinitz H et al. Meta-analysis of neoadjuvant treatment modalities and definitive
CC E
non-surgical therapy for oesophageal squamous cell cancer. Br J Surg 2011; 98: 768-783
[24]. Markar SR, Gronnier C, Pasquer A et al. Role of neoadjuvant treatment in clinical T2N0M0 oesophageal cancer: results from a retrospective multi-center European study. Eur J Cancer 2016; 56: 59-68
A
[25]. Nygaard K, Hagen S, Hansen HS, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992; 16: 1104-1109 [26]. Apinop C, Buttisak P, Preecha N. A prospective study of combined therapy in esophageal cancer. Hapatogastroenterology 1994; 41: 391-393 [27]. Le Prise E, Etienne PL, Meunier B, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994; 73: 1779-1784
14
[28]. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462-467 [29]. Urba SG, Orringer MB, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001; 19: 305-313 [30]. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. N Engl J Med 1997; 337: 161-167 [31]. Lee JL, Park SI, Kim SB, et al. A single institutional phase III trial of preoperative chemotherapy with
IP T
hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 2004; 15: 947-954
[32]. Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery
SC R
for resectable cancer of the oesophagus: a randomized controlled phase III trial. Lancet oncol 2005; 6: 659668
[33]. Natsugoe S, Okumura H, Matsumoto M, et al. Randomized controlled study on preoperative
U
chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer In a single
N
institution. Dis Esophagus 2006; 19: 468-472
[34]. Van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or
A
junctional cancer. N Engl J Med 2012; 366: 2074-2084
M
[35]. Ariga H, Nemoto K, Miyazaki S, 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;
ED
75: 348-356
[36]. Peng L, Xie TP, Han YT, et al. Randomized controlled study on preoperative concurrent chemoradiotherapy
PT
versus surgery alone for esophageal squamous cell carcinoma. Tumor 2008; 28: 620-622 [37]. Fiorica F, Di Bona D, Schepis F, et al. Preoperative radiochemotherapy for oesophageal cancer: a systematic
CC E
review and meta-analysis. Gut 2004; 53: 925-930 [38]. Saeki H, Morita M, Nakashima Y, et al. Neoadjuvant chemoradiotherapy for clinical stage II-III esophageal squamous cell carcinoma. Anticancer Res 2011; 31: 3073-3077
[39]. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil,
A
radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 2008; 26: 1086-1092
[40]. Kaklamanos IG, Walker GR, Ferry K, et al. Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials. Ann Surg Oncol 2003; 10: 754761 [41]. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003; 185; 538-543
15
[42]. Sjoquist KM, Burmeister BH, Smithers BM, eta l. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011; 12: 681-692 [43]. Oppedijk V, van derGaast A, van Lanschot JJ, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol 2014; 32: 385-391 [44]. Shapiro J, van Lanschot JJ, Hulshof MC, van der Gaast A. Effectiveness of neoadjuvant chemoradiotherapy for early-stage esophageal cancer. J Clin Oncol 2015 Jan 20; 33(3): 288-9
IP T
[45]. Czito B, Palta M, Willett C. Results for the FFCD 9901 trial in early-stage esophageal carcinoma: is it really about neoadjuvant therapy? J Clin Oncol 2014; 32: 2398-2400
[46]. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without
SC R
preoperative chemotherapy in oesophageal cancer: a randomized controlled trial. Lancet 2002; 359: 1727-1733 [47]. Wang C, Ding T, Chang L. A randomized clinical study of preoperative chemotherapy for esophageal carcinoma. Zhonghua Zhong Liu Za Zhi 2001; 23: 254-255
U
[48]. Schlag PM. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The
N
Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg 1992; 127: 1446-1450
A
[49]. Maipang T, Vasinanukorn P, Peptichetchian C, et al. Induction chemotherapy in the treatment of patients with
M
carcinoma of the esophagus. J Surg Oncol 1994; 56: 191-197 [50]. Law S, Fok M, Chow S, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell
ED
carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997; 114: 210-217 [51]. Baba M, Natsugoe S, Shimada M, et al. Prospective evaluation of preoperative chemotherapy in resectable
PT
squamous cell carcinoma of the thoracic esophagus. Dis Esophagus 2000; 13: 136-141 [52]. Ancona E, Ruol A, Santi S, et al. Only pathologic complete response to neoadjuvant chemotherapy improves
CC E
significantly the long-term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer 2001; 91: 2165-2174
[53]. Allum WH, Stenning Sp, Bancewicz J, Clark PI, Langley RE. Long-term results of a randomized trial of
A
surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009; 27: 5062-5067
[54]. Boonstra JJ, Kok TC, Wijnhoven BP, et al. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer 2011; 11: 181 [55]. Kelsen DP, Winter KA, Gunderson LL, et al. 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 2007; 25: 3719-3725
16
[56]. Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988; 96: 242-248 [57]. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998; 339: 1979-1984 [58]. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011; 29:
IP T
1715-1721 [59]. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11-20
SC R
[60]. Stahl M, Walz MK, Stuschke M, et a. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009; 27: 851-856
U
[61]. Burmeister BH, Thomas JM, Burmeister EA, et al. Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomized phase II trial. Eur J Cancer
N
2011; 47: 354-360
A
[62]. Leong T, Smithers BM, Haustermans K et al. TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results
M
from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG. Ann Surg Oncol 2017; 24:2252-2258
ED
[63]. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345; 725-730
PT
[64]. Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin
CC E
Oncol 2012; 30: 2327-2333
[65]. Teniere P, Hay JM, Fingerhut A, Fagniez PL. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus As shown by a multicenter controlled trial. French University Association for Surgical Research. Surg Gynecol Obstet 1991; 173: 123-
A
130
[66]. Arnott SJ, Duncan W, Gignoux M, et al. Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal cancer Collaborative Group). Int J Radiat Oncol Biol Phys 1998; 41: 579-583 [67]. Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2010, Issue 1. Art No.: CD002092
17
[68]. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999; 281: 1623-1627 [69]. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002; 20(5): 1167-1174 [70]. Chiu PW, Chan AC, Leung SF, et al. Multicenter prospective randomized trial comparing standard esophagectomy with chemoradiotherapy for treatment of squamous esophageal cancer: early results from the
IP T
Chinese University Research Group for esophageal Cancer (CURE). J Gastrointest Surg 2005; 9: (6): 794-802 [71]. Conroy T, Galais MP, Raoul JL, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and
SC R
cisplatin in patients with esophageal cancer: final results of a randomized, phase 2/3 trial. Lancet Oncol 2014; 15: 305-314
[72]. Merten EV, van Rij C, Tesselaar ME, et al. Definitive concurrent chemoradiotherapy (CRT) with weekly paclitaxel and carboplatin for patients (pts) with irresectable esophageal cancer: a phase II study (abs). J Clin
U
Oncol 2010; 28(suppl): Abs e14508
N
[73]. Ruppert BN, Watkins JM, Shirai K, et al. Cisplatin/paclitaxel as definitive chemoradiotherapy for
A
locoregionally advanced esophageal cancer. Am J Clin Oncol 2010, 33: 346-352 [74]. Wang H, Ryu J, Gandara D, et al. A phase II study of paclitaxel, carboplatin, and radiation with or without
M
surgery for esophageal cancer. J Thorac Oncol 2007; 2: 153-157 [75]. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally
ED
advanced squamous cell carcinoma of the esophagus. J Clin Oncol 2005; 23: 2310-2317 [76]. Bedenne L, Michel P, Bouche O, et al. Chemoradiation followed by surgery compared with chemoradiation
PT
alone in squamous cancer of the esophagus. FFCD 9102: J Clin Oncol 2007; 25: 1160-1168 [77]. Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus
CC E
chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010 Aug 28; 376(9742):687-97
[78]. Pravettoni G, Mazzocco K, Gorini A et al. Understanding cognitive processes behind acceptance or refusal of
A
phase I trials. Critical reviews in oncology/hematology 2016; 100: 69-73
[79]. Kondylakis H, Koumakis L, Tsiknakis M et al. Smart recommendation services in support of patient empowerment and personalized medicine. In Multimedia Services in Intelligent Environments. Springer International Publishing 2013; 39-61 [80]. Kondylakis H, Koumakis L, Genitsaridi E et al. IEmS: A collaborative environment for patient empowerment. In Bioinformatics & Bioengineering (BIBE), 2012 IEEE 12th International Conference 2012; 535-540
18
[81]. Hingorani M, Crosby T, Maraveyas A et al. Neoadjuvant Chemoradiotherapy for Resectable Oesophageal and Gastro-oesophageal Junction Cancer – Do we need another randomised trial? Clin Oncol (R Coll Radiol) 2011
A
CC E
PT
ED
M
A
N
U
SC R
IP T
Dec; 23(10):696-705
19