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Cochrane Database of Systematic Reviews Protocol - Intervention

Perioperative chemotherapy versus primary surgery for locoregionally advanced resectable adenocarcinoma of the stomach, gastroesophageal junction and lower esophagus

Authors' declarations of interest

Version published: 07 October 2009 Version history

https://doi.org/10.1002/14651858.CD008107

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view the current version 31 May 2013
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The primary objective of the present systematic review is to assess if perioperative chemotherapy for patients with locoregionally advanced resectable adenocarcinoma of the stomach, gastroesophageal junction and lower esophagus leads to a longer overall survival as compared to surgery without prior tumor‐specific therapy. Secondary objectives are to compare disease‐free survival, resectability, tumor stage upon resection, perioperative morbidity and mortality between patients with and without perioperative chemotherapy and to assess its safety and toxicity as well as reasons for possible non‐administration of the postoperatively planned cycles of chemotherapy where foreseen in the study protocol.

Background

Description of the condition

The epidemiology of adenocarcinoma of the stomach, gastroesophageal junction and esophagus has changed in recent years. Incidence and mortality figures for cancers of the distal stomach have decreased in most countries whereas corresponding figures for adenocarcinomas of the esophagus and gastroesophageal junction have risen. Combined, gastroesophageal adenocarcinoma ranks among the most common cancers worldwide with an estimated toll of approximately 1,000,000 deaths per year (DeMeester 2006; Forman 2006; Gallo 2006). In spite of some improvements in the last decades, prognosis of the disease is still poor. When combining all tumor stages, five‐year survival rates rarely exceed 30% (Sant 2009).

Although differences in risk factors and tumor biology exist between adenocarcinomas of the stomach, gastroesophageal junction and esophagus (Marsman 2005), it seems justified to regard them as one clinical entity. A recent analysis on a very large number of patients showed that the degree of efficacy of chemotherapy does not differ for tumors of different origin (Chau 2009). For all mentioned tumor locations, radical surgical resection is the only curative treatment modality. Depending on the exact site, distal or total gastrectomy or esophagectomy, ideally with extensive lymph node dissection, need to be performed (Marsman 2005). Despite the fact that surgical techniques and perioperative management have substantially improved over the last decades (DeMeester 2006; Gallo 2006), five‐year survival of patients with locoregionally advanced disease, i.e. tumors which have reached the subserosal layer of the gastric wall or the adventitial layer of the esophageal wall or which have spread to regional lymph nodes, is only 20% to 30% (Hagen 2001; Siewert 1998).

Description of the intervention

Until recently, the standard treatment for adenocarcinoma of the stomach, gastroesophageal junction and lower esophagus has been primary surgery; that is, resection without prior tumor‐specific therapy. This therapeutic approach is still widely used and, at least optionally, recommended by internationally accepted treatment guidelines (NCCN 2007). In the light of poor survival rates, there has been a strong drive to design new treatment modalities in order to achieve better outcomes for patients with non‐metastasized tumors, and especially for those with locoregionally advanced disease upon diagnosis. A number of phase II studies suggest that perioperative chemotherapy, defined as several cycles of chemotherapy before and, optionally, after surgery, is a promising approach to increase overall and disease‐free survival for patients (Ajani 1995; Kelsen 1996; Ott 2003).

How the intervention might work

There are several proposed mechanisms of how perioperative chemotherapy might improve outcomes. A higher likelihood of tumor‐free resection margins due to preoperative downstaging of the tumor, the elimination of micrometastases before and directly after surgery, and the rapid preoperative improvement of tumor‐related symptoms which leads to better tolerability of the upcoming large surgical intervention might all contribute to higher overall and disease‐free survival (Cunningham 2006; Hartgrink 2004). One concern when administering perioperative chemotherapy is the potentially higher level of treatment‐related morbidity and mortality due to cytotoxic effects, which might be particularly hazardous during and directly after surgical procedures. Most phase II studies have shown that the majority of applied chemotherapeutic regimens have acceptable morbidity and mortality (Ajani 1995; Kelsen 1996), but there have been reports of substantial adverse effects of certain regimens of cytotoxic drugs (Ajani 1993).

Why it is important to do this review

In many institutions, physicians still consider primary surgery without perioperative chemotherapy to be the standard treatment for patients with locoregionally advanced resectable adenocarcinoma of the stomach, gastroesophageal junction and lower esophagus. The reason is conflicting evidence, with positive as well as negative results reported from trials assessing the effect of perioperative chemotherapy on survival (Boige 2007; Cunningham 2006; Hartgrink 2004; Nio 2004; Wang 2000). A prior Cochrane Review, published in 2007, summarised the available evidence on the topic (Wu 2007). The authors did not find significant differences in survival between patients treated with neoadjuvant chemotherapy and operated without prior chemotherapy. The authors excluded, however, studies in which patients had received additional postoperative chemotherapy and studies including patients with adenocarcinomas of the esophagus. Thus, the number of included trials was limited to only four. Furthermore, after the authors carried out their literature search in mid‐2005, results of two large randomized controlled trials (RCTs) showing significant survival benefits for perioperative chemotherapy were published Boige 2007; Cunningham 2006. This review has meanwhile been withdrawn on methodological grounds. Therefore, a new systematic assessment of perioperative chemotherapy versus primary surgery for patients with locoregionally advanced resectable adenocarcinoma of the stomach, gastroesophageal junction and lower esophagus is needed, including the recently published data as well as trials on patients with adenocarcinoma of the esophagus and gastroesophageal junction.

Objectives

The primary objective of the present systematic review is to assess if perioperative chemotherapy for patients with locoregionally advanced resectable adenocarcinoma of the stomach, gastroesophageal junction and lower esophagus leads to a longer overall survival as compared to surgery without prior tumor‐specific therapy. Secondary objectives are to compare disease‐free survival, resectability, tumor stage upon resection, perioperative morbidity and mortality between patients with and without perioperative chemotherapy and to assess its safety and toxicity as well as reasons for possible non‐administration of the postoperatively planned cycles of chemotherapy where foreseen in the study protocol.

Methods

Criteria for considering studies for this review

Types of studies

The review will only include RCTs. Due to the specific intervention under study, blinding and placebo treatment are technically and/or ethically impossible because the unavoidable delay of surgery in a study arm where subjects receive a "neoadjuvant" placebo treatment would indubitably lead to a significant worsening of their survival. Therefore, we will not consider blinding and placebo treatment a criterion for inclusion or exclusion.

Types of participants

To be included in the review, trials need to be conducted on patients fulfilling the following criteria:

  • histologically confirmed adenocarcinoma of the stomach, gastroesophageal junction or esophagus;

  • previously untreated;

  • locoregionally advanced (UICC stage Ib and higher for adenocarcinoma of the stomach, UICC stage II for adenocarcinoma of the esophagus (Sobin 2002));

  • resectable based on staging exams;

  • absence of distant or peritoneal metastases.

The specified cut‐off point in UICC stage is chosen because tumors in stage Ib or higher are associated with a substantially poorer prognosis as compared to stage Ia carcinomas (Kikuchi 2001).

Types of interventions

The experimental intervention in the context of this systematic review is defined as surgery in curative intention combined with perioperative chemotherapy, defined as a treatment regimen with any kind of cytotoxic/antineoplastic drug or a combination of several of these drugs. To be regarded as perioperative, chemotherapy needs to be administered in a neoadjuvant (preoperative) setting, and, optionally, in an additional adjuvant (postoperative) manner. We will also include studies if patients receive pre‐ or postoperative radiotherapy in addition to perioperative chemotherapy. We define the control intervention as surgery with curative intention without any prior tumor‐specific therapy, and will include patients undergoing any surgery with curative intent.

Types of outcome measures

Primary outcomes

The primary outcome will be time to death measured in days from the date of randomization, based on an intention‐to‐treat analysis. If censored time‐to‐event data are not available from the single trials, we will use vital status (alive or deceased) at the end of follow up.

Secondary outcomes

Secondary outcomes will be:

  • disease‐free survival time, measured in days from the date of the operation;

  • presence of a tumor‐free resection margin, as assessed from the surgical specimen by a pathologist (dichotomous outcome yes/no);

  • tumor stage at resection, as assessed from the surgical specimen according to the UICC's TNM (T1‐4, N0‐3, M0‐1) classification (Sobin 2002) by a pathologist;

  • safety of the perioperative chemotherapy regimen measured by toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) ;

  • perioperative morbidity (measured by assessing how many of the following events occurred: anastomotic leakage, postoperative pneumonia, postoperative wound infection) and mortality (measured by assessing if a patient died during surgery or the consecutive hospital stay).

  • the reason(s) for possible non‐administration of the postoperatively planned cycles of chemotherapy where foreseen in the study protocol. This will be a non‐comparative analysis performed only in the intervention groups.

Search methods for identification of studies

Electronic searches

We will perform a computerized literature search in the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Review of Effectiveness (DARE), the Cochrane Database of Systematic Reviews (CDSR) from The Cochrane Library, MEDLINE (1966 to present), and EMBASE (1980 to present), LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), and we will limit our search to studies in humans. There are no language restrictions for either searching or trial inclusion.

We will combine the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE, Sensitivity maximizing version, Ovid format (Higgins 2008), with the following search terms to identify randomized controlled trials in MEDLINE. We will adapt the MEDLINE search strategy for use in the other databases searched.

Moreover, we will search the following online databases of ongoing trials:

Searching other resources

Handsearching

We will handsearch the abstracts from 1995 to 2008 of the American Digestive Disease Week (DDW) published in Gastroenterology, the United European Gastroenterology Week (UEGW) published in Gut and the Annual Meetings of the American Society of Clinical Oncology (ASCO) published in the Journal of Clinical Oncology. We will scan reference lists of retrieved articles to identify further relevant trials. We will contact known experts in the field about any unpublished or ongoing studies; also, we will ask the authors of trial reports published only as abstracts to contribute full data sets or completed papers.

We will combine Cochrane Highly Sensitive Search Strategy phases one, two and three (Higgins 2008) with a specialized search to identify randomized controlled trials.

Data collection and analysis

Selection of studies

Two independent reviewers will extract the data. They will assess title, keywords and abstracts of all studies retrieved with the search strategy described above. If, based on this information, we believe studies meet the defined inclusion criteria, we will retrieve and further assess the full text. In cases where one reviewer believes a specific study meets the inclusion criteria for the review whereas the other reviewer does not, we will ask a third reviewer to act as arbiter.

Data extraction and management

The authors will use a standardized data extraction form to compile and document relevant facts on general study characteristics, study quality, patients' characteristics, interventions and outcomes as specified above. We will perform this data extraction independently.
The data extraction form will compile the following items.

  • General information on the study: title, authors, contact address, funding sources, language, publication status, year of publication, place(s) and year(s) of study conduction.

  • Study design issues: in‐ and exclusion criteria, randomization/quasi‐randomization, concealment of treatment allocation (adequate/unclear/inadequate/not used), length of study/follow‐up period.

  • Baseline characteristics of participants: size of intervention and comparison group and for each group the distribution of age, sex, comorbidity (measured, if given as World Health Organization (WHO) performance status or American Society of Anesthesiologists (ASA) classification), tumor location (esophagus, gastroesophageal junction, stomach), and tumor stage (TNM and UICC stage).

  • Characteristics of the intervention: used chemotherapeutic/antineoplastic drugs, regimens (frequency of chemotherapy, timing in relation to the date of surgery, application mode, cumulative dose of chemotherapy planned and administered both pre‐ and postoperatively).

  • Frequency of different types of surgery (approach, extent) performed in the intervention and control groups.

  • Loss to follow up in each group.

  • Outcomes in each group: hazard ratios (HRs) and confidence intervals (CIs) both for overall and, if available, disease‐free survival; number of events (death, disease recurrence) if HRs are not given (in this case they will be estimated according to Parmar et al (Parmar 1998); number of resections with tumor‐free margins; tumor stage at resection (TNM and UICC stage); toxicity according to CTCAE (number of grade 3/4 adverse events); hospital mortality; morbidity as the number of the following events combined: anastomotic leakage, postoperative pneumonia, postoperative wound infection.

We will pilot test the data extraction form on five retrieved studies and, if needed, revise it. Two authors will perform data extraction independently, and consult a third author if arbitration is required to reach consensus.

Assessment of risk of bias in included studies

Both independent reviewers will assess study quality with regard to selection bias, performance bias, attrition bias, and detection bias. We will assume selection bias if the study was either quasi‐randomized or concealment of treatment allocation was unclear, inadequate or not used. For the items performance bias, attrition bias and detection bias, the assessing author will state if bias must be assumed or not. Based on this assessment, the author will assign an overall level of risk of existing bias to each study (low if no bias is assumed, moderate if bias is assumed in one or two items, high if bias is assumed in three or four items). We will use this bias level as a measurement of the quality of each study in sensitivity and subgroup analyses (see below).

Measures of treatment effect

We will measure the effect of the intervention on overall and disease‐free survival with HRs. We will measure its effect on the presence of tumor‐free resection margins, a binary outcome, with an odds ratio (OR). We will treat tumor stage upon resection as binary data by dichotomizing T stage (1/2 versus 3/4) and N stage (0 versus 1/2) and calculating ORs. We will measure toxicity by the mean difference of the total number of CTCAE grade 3/4 adverse events as well as of the single events. We will compare hospital mortality by an OR and morbidity, measured as the number of events specified above, by the mean difference.

Dealing with missing data

We will perform analyses with results from intention‐to‐treat analysis if provided in the single studies. For missing statistics, we will try to contact the authors of the single studies and ask them for the specific values.

Assessment of reporting biases

To assess possible publication bias, if the number of included studies is sufficient, we will create a funnel plot using the different outcomes and evaluate funnel asymmetry with Begg's and Egger's tests (Begg 1994; Egger 1997).

Data synthesis

We will synthesize all data by performing a meta‐analysis with random‐effects models. The usage of random‐effects models is preferred to that of fixed‐effect models because we must assume that non‐explainable heterogeneity between the 'true' effects of the different treatment regimens implied in the trials exists.

Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analyses for the different tumor sites (lower esophagus, gastroesophageal junction, stomach) and for the schemes of the perioperative chemotherapeutic regimen (pre‐operative only versus pre‐operative and post‐operative combined; platinum‐containing regimens versus others; anthracyclin‐containing regimens versus others; protocols including radiotherapy versus pure chemotherapeutical protocols). We will assess heterogeneity clinically (by the judgment of the two independent reviewers), as well as through the calculation of an I2 statistic which is a measure for the percentage of the variability in‐effect estimates attributed to heterogeneity rather than sampling error. If heterogeneity between the effects of the single therapeutic regimens is shown to be too large, i.e. relevant clinical differences or an I2 of above 0.5, we will not do a pooled analysis including all trials. We will do subgroup analyses based on the risk of bias assigned to studies as described above (low, moderate, high).