PDF
ePub
Citation
Print
Introduction
1. Gastric cancer
Tumors of the upper gastrointestinal tract are among the most common malignancies. Approximately 700,000 people die annually of gastric cancer worldwide.1
Fifteen years ago, the 5-year survival rate for advanced gastric cancer was approximately 25% in Europe.2 The current prognosis for 5-year survival is 25% to 30% if perioperative, preoperative, and postoperative (radio-) chemotherapy protocols are administered.
2. The importance of guidelines
Between 400,000 and 1 million controlled studies are carried out internationally each year. This large volume of studies complicated the extraction of the necessary information for any study/research. Guidelines are designed to facilitate medical decision-making within the framework of efficient patient treatment and are fundamental components of quality assurance and management. They must include external scientific knowledge to be able to serve as reliable bases for physician and patient decision-making. This requires systematic research and evaluation of the literature on the different indications. The methodical quality of the studies on which guidelines are based is referred to as the 'level of evidence,' as shown in Table 1.3,4,5
After analyzing the evidence, concrete guideline recommendations are derived from the literature and assigned graduated recommendations. Potential conflicts of interest must be disclosed. Guidelines should be regularly revised and the duration of their validity provided.5
Since the beginning of the 1990s, specialist organizations in different countries have developed guideline programs to ensure and improve the provision of healthcare. The USA, Canada, New Zealand, and Scotland were among the first countries to develop guidelines. In Germany, guidelines have been developed since 1993.
Materials and Methods
For the selection of the guidelines we made some inclsusion criteria to chose them. The guidelines must be available in English or German and based on scientific literature. To guarantee that the content and time interval of the guidelines were comparable, only guidelines published after January 1, 2010, with tumor classification according to the seventh edition of the TNM system (2010) were included.
The systematic literature search was conducted with Ovid. The databases Medline, Cochrane Database, Embase, and PubMed were examined. The search terms used were 'guidelines gastric cancer,' 'guidelines stomach cancer,' and 'Leitlinien Magenkarzinom.' The following websites, medical institutions, and specialist societies were also evaluated: www.leitlinien.de, www.AWMF.org, www.g-i-n.net, and www.guideline.gov.
Results
The results of an examination of the therapeutic recommendations from the assessed guidelines are shown below.
The German S3 guidelines recommend operating on all potentially resectable tumors (T1~T4). Category T1 tumors should only be treated operatively. Perioperative chemotherapy can be administered for T2 tumors. Perioperative chemotherapy should be administered for localized uT3 or resectable uT4a gastric cancer and adenocarcinomas of the esophagogastric junction. Adenocarcinomas of the esophagogastric junction require a perioperative chemotherapy or a perioperative radiochemotherapy. A D2 lymphadenectomy is the standard surgical therapy with curative intention.
The British guidelines of the Department of Surgery, Royal Marsden National Health Service Foundation Trust recommend surgical treatment for resectable gastric cancers. Perioperative chemotherapy is the standard accompanying therapy. Postoperative adjuvant radiochemotherapy can be administered if no preoperative chemotherapy was administered or if surgical tumor reduction was insufficient. A D2 lymphadenectomy is standard surgical therapy with curative intention.
The guidelines of the European Society for Medical Oncology (ESMO) recommend surgical resection for T1b to T3 tumors. A D2 lymphadenectomy is standard for surgical therapy with curative intention. Perioperative chemotherapy is recommended for tumor stages >T1N0.
The American guidelines of the National Comprehensive Cancer Network (NCCN) recommend surgical treatment for all resectable gastric cancers of stages T1 to T4 without metastases in other organs. Regardless of the presence of lymph node metastases, perioperative chemotherapy or postoperative adjuvant radiochemotherapy should be administered for localized gastric cancers. Preoperative radiochemotherapy is recommended for carcinomas of the esophagogastric junction. However, postoperative adjuvant chemotherapy is only recommended for patients who underwent D2 lymphadenectomy, which is the standard surgical treatment with curative intention.
The Canadian guidelines of the Alberta Health Services also recommend surgical removal of all resectable gastric cancers without metastases in other organs. T1 tumors without lymph node metastases require only surgical resection. T2 tumors without lymph node metastases and T1 tumors with lymph node metastases to one or two local lymph nodes should receive postoperative adjuvant radiochemotherapy in addition to surgical resection. All other operable gastric cancers without metastases in other organs should be treated with postoperative adjuvant radiochemotherapy or perioperative chemotherapy. D1 lymphadenectomy is the standard surgical treatment with curative intention.
The Japanese guidelines of the Japanese Gastric Cancer Association (JGCA) recommend surgical treatment of all resectable gastric cancers without metastases in other organs. T1 and T2 tumors without lymph node metastases and T1 tumors with metastasis in one or two local lymph nodes require no accompanying therapy. Advanced stage T3 and T4 tumors require postoperative adjuvant chemotherapy following tumor resection. D1 lymphadenectomy should be performed for T1 tumors without lymph node metastases. A modified D2 lymphadenectomy is the standard procedure for more extensive gastric tumors resected with curative intention.
Table 3 provides an overview of the recommendations of different guidelines for accompanying therapy for advanced gastric cancers.
Due to the inhomogeneity of therapy guidelines, we examined the scientific data on which the various guidelines are based by evaluating the literature.
1. Literature on which the German guidelines are based
Recommendations for perioperative chemotherapy for advanced gastric cancer were based on three studies. When the commission created this guideline in 2010, only the British MAGIC study was available in its entirety. This study was considered a pioneer in perioperative chemotherapy. Cunningham et al.12 reported an improvement of 12.5% in the 5-year survival rate.
Their results were confirmed in the French ACCORD study.13 A third study from Germany (EORTC) also verified a benefit in patients receiving perioperative chemotherapy.14
Only abstracts of the two latter studies were available at the time the guidelines were created, resulting in an evidence level of 1b (no meta-analyses).
The 66 guideline experts did not reach an unanimous decision. Fifty percent voted for a level B recommendation due to the identified weaknesses in the cited studies. The MAGIC and ACCORD studies were criticized, above all, for their lack of surgical and pathological quality controls and the fact that only about 50% of the patients in the perioperative-chemotherapy group were able to complete the study according to the protocol. The prematurely terminated EORTC study was criticized for having inadequate power.
Based on Gebski et al.'s meta-analysis15 in 2007, preoperative radiochemotherapy for carcinomas of the esophagogastric junction is recommended as an alternative to perioperative chemotherapy alone.
In contrast, preoperative radiochemotherapy for the treatment of gastric cancer was explicitly rejected in the German S3 guidelines. Due to the small number of cases and absence of a control group, there are no valid data for this kind of accompanying therapy. The adverse effects of preoperative radiochemotherapy also contribute to deterioration in the patient's health status.16,17
In addition, evidence supporting the administration of postoperative adjuvant chemotherapy is insufficient, even if a marginal survival advantage was demonstrated in a meta-analysis of patients receiving postoperative treatment.18,19,20,21,22
There is no standard for postoperative adjuvant radiochemotherapy following R0-resection and sufficient lymphadenectomy. Studies conducted to clarify this indication showed a certain survival advantage for patients treated with postoperative radiochemotherapy,23,24 but a D2 lymphadenectomy was performed in only a few patients, and no definitive statement can be made while maintaining a high surgical standard.
Both postoperative adjuvant procedures could be considered for patients at high risk of recurrence and who received no preoperative therapy.
2. Literature on which the British guidelines are based
The British guideline also based its recommendations for perioperative chemotherapy on the MAGIC study12 and the abstract of the ACCORD study.13 The two studies claimed a survival advantage of 12.5% and 14%, respectively.
Meta-analyses, particularly from Asian countries,18,25,26 were able to demonstrate a certain survival advantage after administration of postoperative adjuvant chemotherapy. However, postoperative adjuvant chemotherapy is not a standard approach following stomach resection with curative intention and should only be used in patients at high risk of recurrence who did not receive preoperative chemotherapy.
Postoperative adjuvant radiochemotherapy has been used, especially in the USA, following the publication of the Intergroup 0116 Trial study.23 However, this should only be considered for patients at high risk of recurrence and no preoperative therapy. The patients of the UK are not comparable with the patients of the intergroupstudy because of the great differences to make the lymphadenectomy.
3. Literature on which the European Society for Medical Oncology guidelines are based
These guidelines also cite the MAGIC12 and ACCORD13 studies conducted in patients receiving perioperative chemotherapy. Perioperative chemotherapy has become the standard therapy for gastric cancer in large parts of Europe and Great Britain.
It remains unclear whether postoperative adjuvant chemotherapy or radiochemotherapy provides better therapeutic success. The results of the CRITICS study27 should clarify this question. In contrast to the USA,28 there are no clear recommendations for postoperative adjuvant radiochemotherapy in Europe because the surgical quality in Europe is higher and the dangers of toxic side effects are taken more seriously.
According to a current meta-analysis, only a very small benefit is derived from postoperative adjuvant chemotherapy in Europe compared to Asian countries,29,30 even though Global Advanced/Adjuvant Stomach Tumor Research International Collaboration (GASTRIC) Group's meta-analysis19 demonstrated a marginal survival benefit of 6.8%.
The ESMO does not discuss preoperative radiochemotherapy.
4. Literature on which the American guidelines are based
The recommendations for postoperative adjuvant radiochemotherapy are based on a phase 3 study by Macdonald et al.23 in 2001, which showed a significant median overall survival of patients receiving postoperative adjuvant radiochemotherapy following surgery. The high number of grade 3 and 4 toxicities was attributed to the administration of currently outdated chemotherapeutic regimes. The recommendations apply particularly to patients undergoing D0 or D1 lymphadenectomies, because the number of patients who underwent D2 lymphadenectomies is too small to provide sufficient power to confirm an advantage in this group. In a follow-up study, the same patients were observed over a period of 10 years. Survival rates remained the same, confirming the results of the study by Macdonald et al.23 The number of patients who experienced late toxic effects did not increase.28
One possible alternative to postoperative adjuvant radiochemotherapy is perioperative chemotherapy.12,13 The authors, however, critically mention that neither the MAGIC nor ACCORD study has sufficient power to evaluate the role of pre- or postoperative adjuvant treatment because D2 lymphadenectomies were not routinely performed.
5. Literature on which the Canadian guidelines are based
Depending on the tumor size, the Canadian guidelines recommend either perioperative chemotherapy or postoperative adjuvant radiochemotherapy. The 5-year survival rate increased from 26% with surgery alone to 40% with postoperative adjuvant radiochemotherapy.23 Perioperative chemotherapy increased the 5-year survival rate to 36.3% compared with the 23% after surgery alone,12 or to 38% compared with the 24% after surgery alone.13
No other accompanying therapies are mentioned in the Canadian guidelines.
6. Literature on which the Japanese guidelines are based
Recommendations for postoperative adjuvant chemotherapy are based on the ACTS-GC3 study, in which the patients treated with postoperative adjuvant therapy after tumor resection had a 3-year survival rate of 80.1% compared to the 70.1% in patients treated with surgery alone.33
Preoperative radiochemotherapy should not be administered except in clinical studies. Although the results of a phase 2 study, in which no vital cells were found in 20% to 30% of patients following preoperative radiochemotherapy, sound promising, they have not been confirmed in randomized studies.17
In contrast to the USA, D2 lymphadenectomies are performed routinely and the standard of surgery is high in Japan; hence, there was no evidence for the effectiveness of postoperative adjuvant radiochemotherapy.23,28 Perioperative chemotherapy has become an established practice in Europe since the publication of the MAGIC study.12 There has been no effect observed in Japan, but perioperative chemotherapy remains an option for patients with poor prognosis and high risk of recurrence.
Table 4 shows the most important studies on which recommendations for or against the investigated therapies are based in the six discussed guidelines.
Discussion
The guidelines examined in this paper were published within the past 5 years, and expert groups had access to comparable sources when developing the guidelines. Therefore, we would expect nearly identical therapy recommendations. A comparison of the guidelines reveals distinct differences. For advanced stages of gastric cancer, there are differing recommendations for perioperative chemotherapy, postoperative adjuvant chemotherapy, perioperative radiochemotherapy, or postoperative adjuvant radiochemotherapy in the individual countries. Recommendations for or against a therapy are based on the same scientific publications.
For example, the Intergroup 0116 study by Macdonald et al.23 published in 2001 was cited in all six guidelines (Table 4), but recommendations for postoperative adjuvant radiochemotherapy based on this study can only be found in the American and Canadian guidelines. These two countries rated the effect of radiochemotherapy higher than its toxicity and the absence of D2 lymphadenectomy. Guideline experts from the other four countries came to a contrary assessment. A comparison of the German S3 guidelines with the British, American, and Scottish guidelines for the diagnosis and treatment of advanced gastric cancer was recently conducted by Moehler et al.37 Regarding the recommendations for perioperative or postoperative adjuvant therapy, they concluded that perioperative chemotherapy has become an established practice in Europe. In the USA, postoperative adjuvant radiochemotherapy is favored, with perioperative chemotherapy considered an alternative therapy.36
Consensus in guideline committees substantially depends on the interpretation of the studies on which the guidelines are based. A reliable interpretation depends on a high degree of validity of these clinical studies. The validity of perioperative chemotherapy studies (MAGIC, ACCORD, and EORTC) was already judged by our group to be limited due to several grave shortcomings.37 Nevertheless, the British MAGIC study was cited in all guidelines examined and, with the exception of Japan, all national guidelines recommended perioperative chemotherapy based on this study. Due to its limited validity, the endpoints of morbidity, mortality, patient satisfaction, and quality of life could hardly be evaluated.
Discrepancies between the guidelines resulted from different interpretations of the same studies. We assume that the decisions were actually based on different value judgments that are influenced not only by scientific evidence, but also by other factors such as public and political opinion, and financial and structural realities. For example, distal cancers are more prevalent in Japan and Korea, and D2 gastrectomy is more easily performed due to the higher volume and greater availability of experienced surgeons, as well as the patients' body habitus.
Treatment of advanced gastric cancer is, therefore, not internationally comparable.
Every country, regardless of size, expends great effort to develop its own guidelines. In the future, an international cooperation should be established to create guidelines.38,39 Each country could contribute to each of the following five steps to provide an international guideline basis. This basis for guidelines would allow each nation to individually evaluate the available scientific evidence, but reduce the huge effort required by each country in the absence of international cooperation.
Countries expend great efforts to collect the questions to be answered in most guidelines, identify relevant literature to answer these questions, and critically evaluate the validity of each publication containing concrete statements supporting a guideline. There is no need to conduct a time-consuming evaluation of a study's validity if it does not concretely provide a recommendation supporting the guideline. If scientific evidence claims to be internationally valid, an international committee should be able to present acceptable studies as valid and formative, eventually creating a basis for international guidelines. These studies would be able to answer some of the initially posed questions. Services not represented in the international guidelines but included in the catalogue of national guidelines would depend on the prosperity and expectations of a country's citizens. Table 5 summarizes the five steps required to create the basis for international guidelines.
Although many of the same study results are used to produce the different guidelines, the rational recommendations for accompanying therapy for advanced gastric cancer vary among countries, sometimes considerably. This is due to discrepancy in the interpretation of the same study results by different countries.
As a great deal of effort is required for each country to separately evaluate the validity and suitability of relevant studies for inclusion in guidelines, international cooperation for the creation of a common basis for guidelines could facilitate their development and contribute to greater comparability.
XML Download