Gastric cancer (GC) is the third most common cancer-related cause of death worldwide. In locally advanced tumors, neoadjuvant chemotherapy has recently been introduced in most international Western guidelines. For metastatic and unresectable disease, there is still debate regarding correct management and the role of surgery. The standard approach for stage IV GC is palliative chemotherapy. Over the last decade, an increasing number of M1 patients who responded to palliative regimens of induction chemotherapy have been subsequently undergone surgery with curative intent. The objective of the present review is to analyze the literature regarding this approach, known as “conversion surgery”, which has become one of the most commonly adopted therapeutic options. It is defined as a treatment aiming at an R0 resection after chemotherapy in initially unresectable tumors. The 13 retrospective studies analyzed, with a total of 411 patients treated with conversion therapy, clearly show that even if standardization of unresectable and metastatic criteria, post-chemotherapy resectability evaluation and timing of surgery has not yet been established, an R0 surgery after induction chemotherapy with partial or complete response seems to offer superior survival results than chemotherapy alone. Additional larger sample-size randomized control trials are needed to identify subgroups of well-stratified patients who could benefit from this multimodal approach.

Gastric cancer (GC) is known to be the third most common cancer-related cause of death worldwide[1]. Surgical treatment with adequate extended lymphadenectomy is associated with good outcomes in early stages. However, in advanced GC, prognosis remains poor. Neoadjuvant chemotherapy (NAC) has been suggested for resectable, locally advanced GC based on well-known Randomized Controlled Trial (RCT)s[2,3]. Despite many enrolled patients having lower esophagus or esophagogastric junction involvement and surgery not always including a standard extended lymphadenectomy, there was a survival advantage of NAC plus surgery compared to surgery alone. Therefore, NAC, or preferably preoperative chemotherapy, has been recently introduced as an option in most treatment guidelines[4-9].

The SEER database shows that one third of Western patients with GC have unresectable disease, and different strategies have recently been adopted to manage advanced unresectable cancer[10]. Generally, in these cases, surgery is upfront considered as a palliative treatment for obstruction or bleeding.

Palliative chemotherapy remains the main treatment strategy of IV stage GC patients[11]. Although the median survival time (MST) of these patients has improved due to development of new chemotherapeutics agents, it is still unsatisfactory. Therefore, patients who demonstrated a response to chemotherapy have begun to be subsequently surgically treated with curative intent. This approach in stage IV patients, called “conversion surgery”, is becoming one of the most common therapeutic options discussed in the literature over the last decades. The aim of the present review was to define the effective usefulness of this strategy, to identify its crucial aspects and to highlight critical issues and implications for future perspectives.

Stage IV GC is a heterogeneous biological condition with a mixture of distant metastases, including hematologic, lymph nodal and/or peritoneal. To reduce this heterogeneity, the Japanese Gastric Cancer Association (JGCA) and the Union Internationale Contre le Cancer (UICC) minimized differences between their classifications and categorized similar groups[12-16]. However, these systems do not seem sufficient to derive any significant clinical suggestions.

In the recent classification introduced by Yoshida et al[17] with the proposal to identify objective principles for conversion surgery, stage IV patients were subdivided into 4 new categories (Figure 1). Initially, the presence of macroscopic peritoneal dissemination is considered as a different biological and prognostic finding compared with hematological metastases. Patients without peritoneal involvement belong to category 1 (potentially resectable metastases) and category 2 (marginally resectable metastases). Patients with macroscopic peritoneal metastases are stratified into category 3 (unresectable except certain situations) and category 4 (incurable metastases). Below we highlight different critical aspects in terms of staging, treatment and prognosis of different potential metastatic patterns in stage IV GC.

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Figure 1 Biological categories proposed by Yoshida et al[17]. GC: Gastric cancer.

As specified above, according to current guidelines, palliative chemotherapy is the main strategy for treatment of stage IV GC patients. These cases have always represented the ideal setting for use of many new combinations of chemotherapeutic agents, both in Japan and in Western countries[55-67]. The median overall survival observed in these studies varies between 3 and 17 mo. In the SPIRIT trial, an overall survival of 13 mo was reported using S-1 plus cisplatin, which is defined as the standard treatment for metastatic GC in Japan[56]. In Western countries, the treatment most commonly used for metastatic GC is a combination of chemotherapy regimens, including fluoropyrimidine plus a platinum agent, though epirubicin or docetaxel can also be combined[64,66]. Recent developments in chemotherapeutic and molecular targeted agents have added new clinical issues in the management of incurable GC. As reported in the ToGA trial, Trastuzumab plus chemotherapy in HER2-positive patients improved overall median survival from 11.1 to 13.8 mo[60]. In addition, histological biomarkers have been identified to predict survival among GC patients[68]. Recently, palliative chemotherapy seemed further validated compared with palliative surgery by results of the REGATTA trial. In fact, although some authors emphasized the beneficial role of palliative gastrectomy[69,70], in this RCT, Fujitani et al[71] demonstrated no survival benefit for palliative gastrectomy prior to chemotherapy in advanced GC patients with a single non-curative factor. However, the methodological biases of the REGATTA trial negatively affect reliability of its results and weaken its potential clinical implications[72]. Therefore, at the moment, for stage IV GC patients, we have no strong evidence to consider the results of palliative chemotherapy satisfactory. On the other hand, we also have no reliable data to suggest definitely abandoning surgery.

The heterogeneous presentation of stage IV GC characteristics makes it difficult to identify the best therapeutic strategy for these tumors due to their different biological behaviors. On the other hand, given the poor results achieved with chemotherapy alone, in order to further improve survival of these patients, new therapeutic approaches have been considered. Based on experiences of the multidisciplinary treatment of metastatic colorectal cancer, in the last 2 decades, many studies have been conducted to evaluate efficacy of the combination of chemotherapy and surgery for stage IV GC. Surgical resection for advanced tumors has historically been called “radical”, “salvage”, “adjuvant” or “secondary” gastrectomy. More specifically, the concept of conversion surgery has been recently treated by Yoshida[17] to define a treatment aiming to R0 resection after chemotherapy in initially unresectable patients.

Tables 1 and 2 show patient characteristics and treatment options analyzed in the considered studies, as well as survival results. Below, we discuss in chronological order the main results of these studies, with particular focus on potential prognostic factors in conversion surgery strategy.

Gastric cancer is known to be a heterogeneous disease. Dissemination may occur directly to the peritoneum, through the hematogenous and lymphatic systems. Moreover, the method whereby cancer cells enter into the portal circulation varies, resulting in significant variability of metastatic patients both for the site and the amount of tumor. Consequently, few metastatic patients are eligible for conversion surgery. Moreover, frequent coexistence of different factors of incurability make it difficult to identify true prognostic variables, as well as the rate of response to chemotherapeutic treatments. Despite progress in chemotherapy providing significant hope with new drug agents, the response rates of metastatic GC patients remain unsatisfactory with non-optimal patient compliance. The definition of initial unresectable criteria and post-chemotherapy resectability has yet to be established. In many cases, the line between neoadjuvant and induction chemotherapy remains unclear. Therefore, analysis of experiences on conversion surgery in stage IV GC is very challenging due to the heterogeneity of series, makes it very difficult to compare results from different studies. Furthermore, the majority of analyzed studies have been performed in Eastern Asia (only one in Italy). As such, this could represent a potential bias for reliable evaluation independent of differences in chemotherapy schedules, quality of surgery, and patient biology, for example. Undoubtedly, the Regatta trial taught us that even a palliative gastrectomy increases patient morbidity compared with chemotherapy alone. Hence, a strict selection of patients who could potentially benefit from conversion surgery seems mandatory. Yoshida et al[17] proposed a biological classification to stratify all stage IV GC patients to respond to this need (Figure 1). Probably, long-term survivors can be found mostly in the first three categories, though the small number of patients in the first category can be explained by this unusual condition. Actually, these patients are likely to benefit from NAC.

Although analyzed studies were retrospective and limited with respect to number of patients enrolled, the possibility of curative resection seems a crucial aspect. The literature reports R0 resection rates ranging from 24%-100% (Table 1), and these numbers are closely correlated with prognosis (Table 2). Thus, the survival benefit derived from R0 resections might justify a predictable increase in morbidity compared with survival from medical therapy alone. Interestingly, even non-curative resection often results in superior survival compared to chemotherapy alone. Consistent with this suggestion from the literature, quality of life (QOL) after conversion (even if non curative) surgery remains an intriguing issue to be analyzed. In this regard, a meta-analysis conducted by Lasithiotakis et al[86] underlined the relevant role of QOL outcomes after palliative gastrectomy.

Consistent with considerations by Yoshida et al[17], the presence of only one-site of metastasis is one of the most important prognostic factors according to most analyzed studies. In this literature review, lymph node metastases and positive cytology on peritoneal washing as unresectable factors are also related to better prognoses after conversion surgery when partial or complete response to chemo was observed. In this regard, while the more reliable (and later) evaluation of pathological response was demonstrated to be correlated with survival after conversion therapy, we have no unquestionable prognostic data and no objective criteria for clinical response assessment. Indeed, another determining factor is the detection of the best timing to operate (or to decide to not operate). Generally, surgery occurs when the tumor decreases in sizes and before it develops any drug resistance. For this determinant decision making step, cooperation between oncologists and surgeons is mandatory for general management of patients (and not the tumor alone). Regarding type of surgery and extension of lymphadenectomy, total or distal gastrectomy (also with multivisceral approach) aiming at R0 resection was generally associated with D2 or more extended lymphadenectomy. We believe that a proper and standardized D2 lymphadenectomy could achieve optimal results with acceptable morbidity/mortality. Finally, whether chemotherapy is required after an R0 resection is an issue that needs clarification.

In conclusion, the survival efficacy of conversion surgery may dramatically improve when combined with targeted chemotherapy. Perhaps new cytotoxic and molecular targeted agents and progress in sensitive molecular biomarker development could shift treatment from standardized to personalized, leading to further improved outcomes. The promising results of this multimodal therapy are increasingly gaining the attention of medical and surgical oncologists in planning further studies. Although it seems hard to design a valuable trial due to the difficulty of enrolling patients, it appears mandatory to demonstrate the effectiveness of this strategy in stage IV GC patients, or at least in well-selected and stratified stage IV patient subgroups. On the other hand, given that long-time survivors exist, we are convinced that the multidisciplinary discussion should always be recommended on a case-by-case basis. In conclusion, it is well known that some decades ago patients affected by unresectable GC represented a large population on whom medical oncologists applied new and promising therapies without great success. Today, the strategy of conversion surgery induces oncologists to consider that surgery could still have a role, even after almost “hopeless” systemic therapy.