Oesophagogastric junction adenocarcinoma: which therapeutic approach?

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Oesophagogastric junction adenocarcinoma: which therapeutic approach? Christophe Mariette, Guillaume Piessen, Nicolas Briez, Caroline Gronnier, Jean Pierre Triboulet Lancet Oncol 2011; 12: 296–305 Published Online November 24, 2010 DOI:10.1016/S14702045(10)70125-X Department of Digestive and Oncological Surgery, University Hospital C Huriez, Lille, France (Prof C Mariette MD, G Piessen MD, N Briez MD, C Gronnier MD, Prof J P Triboulet MD); and Medical Department, University Lille-Nord de France, Lille, France (Prof C Mariette, G Piessen, Prof J P Triboulet) Correspondence to: Prof Christophe Mariette, Department of Digestive and Oncological Surgery, University Hospital C Huriez, Place de Verdun, 59037 Lille, Cedex, France [email protected]

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Gastric and oesophageal cancers are among the leading causes of cancer-related death worldwide. By contrast with the decreasing prevalence of gastric cancer, incidence and prevalence of oesophagogastric junction adenocarcinoma (OGJA) are rising rapidly in developed countries. We provide an update about treatment strategies for resectable OGJA. Here we review findings from the latest randomised trials and meta-analyses, and propose guidelines regarding endoscopic, surgical, and perioperative treatments. Through a team approach, members from all diagnostic and therapeutic disciplines, such as gastroenterologists, surgeons, oncologists, radiologists, and radiotherapists, can effectively administer a range of treatment modalities.

Introduction Although the prevalence of gastric cancer is decreasing, there is an alarming rise in the incidence and prevalence of oesophagogastric junction adenocarcinoma (OGJA) in developed countries.1,2 Many discrepancies exist in the published work about the causes, classification, and surgical and perioperative oncological treatments of these tumours. First, the borderline location of these tumours between the oesophagus and stomach leads to confusion. Second, clinical trials investigating such tumours have been divided between those aimed at treating gastric cancer and those aimed at treating oesophageal cancer; very few randomised studies have treated OGJA as a separate entity. Third, a clear range of tumours arise in the oesophagus, the oesophagogastric junction, and the stomach in terms of epidemiology, genetics, patterns of spread, and prognosis. Fourth, OGJAs might not all be the same disease, which has led to specific classification.3 Therefore, a review and summary of the guidelines about endoscopic, surgical, and perioperative treatments, such as neoadjuvant or adjuvant (radio)chemotherapy, is important for the treatment of patients with OGJA. There is no standardised definition or classification of OGJA. The terms cardia adenocarcinoma, junctional adenocarcinoma, and lower-oesophageal adenocarcinoma encompass tumour types that can differ, and that are, at best, grouped together under the term OGJA. The anatomical and surgical classification of the three types of OGJA, adapted from Siewert and colleagues,3 has allowed resection to be codified and a comparison to be made between surgical series (figure 1). Type I tumours are lower-oesophageal adenocarcinomas, and usually develop on Barrett’s mucosa, type II tumours are true cardia adenocarcinomas, and type III tumours are subcardial adenocarcinomas of the stomach. Such a classification system has been established with data from preoperative morphological assessments and perioperative findings. The main strength of this system is the clarification of various tumour locations, which allows the treatment strategy to be adapted correspondingly. Such clarification is especially useful for the surgical approach, because type I is treated as an oesophageal cancer and type III as a gastric cancer. Some controversy exists for treatment of

type II disease. The disadvantages of this classification system are that it is based on preoperative and perioperative data, so the outcomes cannot be reliably anticipated; it is difficult or impossible to establish if there is a hiatal hernia or an advanced tumour, which are common situations; and the advantage of its prognostic ability has been questioned.4–7 Overall, efforts to classify OGJA has produced two anatomo-clinical entities—tumours that have either oesophageal or gastric locations.

Endoscopic treatment Recent improvements in endoscopic technique have led to increased interest in its application to OGJA. Node-negative T1 tumours are associated with a 5-year overall survival of more than 90% after surgery.8 Endoscopic therapy should be accepted as the treatment of choice in most patients with high-grade intraepithelial neoplasia and mucosal OGJA, because it has the potential to achieve the same curative effect as surgery—that is, it can result in no residual disease and the eradication of the potential underlying premalignant mucosa (Barrett’s oesophagus). Low morbidity and mortality and an improved quality of life as a result of organ preservation are benefits of endoscopic treatment in cases 5 cm

Type I Anatomical cardia 1 cm Type II –2 cm Type III –5 cm

Figure 1: Schematic illustration of the modified Siewert’s classification Distance of centre of tumour from anatomical cardia determines tumour type.

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of early OGJA.9 Ablation techniques have advantages and disadvantages. Photodynamic therapy allows for the successful ablation of both Barrett’s and foci adenocarcinoma, but does not result in pathological specimens from tissue destruction, has variable or imprecise depth of injury, leaves untreated potential lymph nodes, and is associated with substantial risk for persistent or recurrent disease, post-therapeutic fibrotic strictures, or expansiveness.10 Endoscopic mucosal resection seems to be appropriate with precise en-bloc dissection and specimens to analyse, but should also be applied if there is underlying Barrett’s mucosa.10 One phase 3 trial,11 which assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barrett’s oesophagus, had promising results with a high eradication rate and lower disease progression in the treatment group than in the control group and few oesophageal strictures (6%). Proper patient selection is paramount in such a setting. In surgical series, the probability of lymph-node metastasis in early OGJA is associated with an increase in tumour size, submucosal, lymphatic, and vascular invasion, and poor differentiation.12–14 Findings suggest 0% lymph-node involvement in the case of in-situ superficial T1m1 or m2 (invasion of the surface or middle third of the mucous membrane) carcinoma, if small and well-differentiated; nearly 0% lymph-node involvement for m3 OGJA; and 1–3% lymph-node involvement for T1 sm1 (muscularis mucosae superficial layer), but 10–30% lymph-node nvolvement for sm2 and sm3 tumours.12–14 A

Moreover, the clinical condition of the patient, accessibility of the tumour, and available medical expertise should be taken into account. Thus, endoscopic mucosal resection could be proposed for T1m1 to sm1 OGJA, if well-differentiated, not depressed, and smaller than 2 cm. In an invasive lesion on a resected specimen (sm2 or sm3), curative surgery is needed in operable patients because of the high risk of lymph-node involvement.

Surgery The choice of surgical techniques is controversial, with particular uncertainty about the appropriate extent of resection in the oesophagus and the stomach, the extent and the sites of lymphadenectomy, and the optimum surgical approach.

Macroscopic and microscopic complete resection Several studies3,4,7,15–17 have analysed the long-term progress of patients who have been operated on for an OGJA, depending on the type of resection (as defined by the International Union Against Cancer [UICC] criteria).18 5-year overall survival for patients with R0 resection (macroscopically and microscopically complete) ranges from 43% to 49%, compared with 0% to 11% for microscopically incomplete resections (R1) and 0% to 4% for macroscopically incomplete resections (R2). R0 is, therefore, associated with longer survival than is R1 or R2, B

Figure 2: Perioperative view (A) and schematic representation (B) of a gastric pull-up preparation as an oesophageal substitute after resection for type I oesophagogastric junction adenocarcinoma Gastric graft (white arrows) has been largely tubulised (black arrows) and vascularised by right gastroepiploic vessels (red arrows). Figure 2B reproduced with permission from reference 20.

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and constitutes the principal independent prognostic factor in multivariate analysis in most studies.3,4,7,17 Furthermore, palliative surgery (R1 or R2), in addition to having a higher associated morbidity and mortality than R0 surgery, does not bring any benefit when compared with exclusive medical treatments.15,17,19

Mediastinal dissection Whether or not mediastinal dissection is done, its extent is often confused with the surgical approach (figure 2). Two principal approaches for superior polar oesogastrectomy are the right-transthoracic approach, with an anastomosis at the top of the thorax (figure 3) or in the cervical area, and the transhiatal approach, with a cervical anastomosis, without thoracotomy. A third surgical approach, which is less-commonly used, is the left thoracophrenolaparotomy.22 The transthoracic approach allows for improved intrathoracic tumour and lymph-node dissection, reducing the risk of damage to adjacent organs,23 and therefore improves tumour staging and locoregional control. The transhiatal approach seems to reduce respiratory complications, causes less serious fistulae, and reduces the operating time, resulting in decreased postoperative morbidity and mortality.23 Finally, the left thoracophrenolaparotomy approach allows for a satisfactory abdominal and thoracic opening to be obtained with a single incision; however, undertaking an anastomosis under the aortic arch causes a high rate of reflux and a limited proximal margin. Only one randomised trial,24 of 220 patients who had surgery for OGJA, has compared en-bloc transhiatal oesophagectomy with abdominal and lower-mediastinal dissection with a three-field transthoracic oesophagectomy with two-field lymphadenectomy. The rate of R0 resection was 72% in the transhiatal group compared with 71% in the transthoracic group (p=0·28), with a mean number of dissected lymph nodes of 16 (SD 9) versus 31 (14; p<0·001),

A

respectively. Postoperative mortality did not differ significantly between the two groups (2% vs 4%; p=0·45), whereas respiratory morbidity was significantly increased in the transthoracic group (57% vs 27%; p<0·001). Incidence of fistula did not differ between groups (14% vs 16%, p=0·85) and nor did recurrent nerve palsy (13% vs 21%, p=0·15). A non-significant pattern of improved 5-year overall survival was noted in the transthoracic group compared with the transhiatal group (39% vs 29%), and in disease-free survival (39% vs 27%). A subgroup analysis indicated a gain in 5-year overall survival of 17% in the transthoracic group for patients with type I OGJA, compared with only 1% for those with type II OGJA. The long-term results confirmed these data, with 5-year survival of 34% in the transhiatal group versus 36% in the transthoracic group (p=0·69), but a gain in survival of 14% for type I OGJA.25 A randomised trial of type II and type III OGJA compared total gastrectomy by laparotomy (with partial oesophagectomy) with a left thoracophrenolaparotomy.22 Findings from the interim analysis showed that the rate of R0 resection was comparable between the two groups (76% in the abdominal group vs 75% in left thoracophrenolaparotomy group), with a 5-year overall survival of 52·3% in the abdominal group compared with 37·9% in the left thoracophrenolaparotomy group (non-significant), and increased postoperative morbidity (especially respiratory morbidity) in the left thoracophrenolaparotomy group (49% vs 34%; p=0·06). In OGJA, resection by left thoracophrenolaparotomy is therefore not recommended. Two retrospective studies of more than 1000 patients have been published on OGJA with a consensual surgical strategy for type I tumours (superior polar oesogastrectomy via the transthoracic approach) and type III tumours (total gastrectomy via laparotomy), but different strategies for type II tumours. For type II tumours, Siewert and colleagues3,17 proposed a total gastrectomy with partial oesophagectomy, using the

B

Figure 3: Perioperative view (A) and schematic representation (B) of intrathoracic oesophageal dissection for type I oesophagogastric junction adenocarcinoma White arrows show tumour, blue arrows shows rachis, grey arrows show pericardium, green arrows show lung, and black arrows show trachea. Figure 3B reproduced with permission from reference 21.

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transhiatal approach, because of lymph-node tropism (which is essentially abdominal for type II) and the absence of any advantage in terms of survival for superior polar oesogastrectomy via the transthoracic approach (which also has increased morbidity). Superior polar oesogastrectomy via the transhiatal approach was done if the R0 resection was not feasible via the abdomen alone.3,17 In a French multicentre investigation, a lower rate of R0 resection was noted for advanced type II OGJA (T3 or T4) in the event of total oesogastrectomy than for superior polar oesogastrectomy (64·6% vs 78·7%), with no significant difference in terms of postoperative morbidity and mortality. A total gastrectomy did not, therefore, provide any benefits in terms of radicality, whatever the size of the tumour. For large tumours, superior polar oesogastrectomy was more radical than were other procedures because of a large proximal margin. Therefore, this intervention can be recommended.7,26

Abdominal dissection There is a general consensus that total gastrectomy with oesophago-abdominal resection, and D2 lymphadenectomy via laparotomy should be used for type III tumours and gastric cancer.3,4,7,27 Extensive lymph-node dissection, such as para-aortic dissection, increases morbidity without survival benefit in patients with gastric cancer.28,29 Martin and colleagues29 showed the advantage of enlarging en-bloc resection to the nearby organs for type II and III OGJA. The study compared 865 nonextended gastrectomies with 268 extended gastrectomies. No difference was noted in operative mortality, with a better median overall survival in the event of nonextended resection (63 months vs 32 months, p<0·01); however, a notable 5-year overall survival of 32% was reported after extended dissection for locally advanced tumours. These findings were confirmed in another study of 1192 patients.7

Laparoscopy In the late 1990s, investigators at several centres began exploring the potential of a minimally invasive oesophagectomy or gastrectomy. Techniques have now been developed for laparoscopic and thoracoscopic approaches, separately or in combination.30 No randomised trial has yet been published about the effect of minimally invasive techniques for oesophageal, OGJA, or proximal gastric tumours. However, an ongoing phase 3 multicentre trial might provide strong data in the near future.31 On the basis of the surgical information discussed, several surgical carcinological recommendations can be made (panel, figure 4). In all cases, the aim is for complete R0 resection. After surgery with recommended lymphadenectomy, 5-year overall survival has been reported at 37% for stages pT3–T4, 38% for pN+, 56% for stage II, 46% for stage III, and 11·6% for stages IIIB and IV.32 Locoregional, www.thelancet.com/oncology Vol 12 March 2011

peritoneal, and distant recurrences have been reported in 32·5%, 45·9%, and 34·2% of cases, respectively.32 After R0 resection, the two principal predictive factors of recurrence are lymph-node involvement and tumoural invasion beyond the muscularis mucosae. According to Siewert’s classification, 5-year survival is around 40% for type I, 30% for type II, and 25% for type III.3,5,7 Thus, most patients who undergo surgery (apart from Japan7) present an OGJA at a stage of at least type II; the risk of relapse is more than 50%.

Combination of surgery and neoadjuvant or adjuvant treatments Chemotherapy and radiotherapy could improve the control of the disease by downstaging cancer, and thereby increasing resectability via the eradication of micrometastastic disease, the decrease in cancer-cell dissemination during intervention, and by complementing another treatment modality without affecting postoperative mortality and morbidity.

Postoperative chemotherapy versus surgery alone In view of the high incidence of local recurrences and distant metastases, different adjuvant chemotherapy protocols have been compared with surgery alone in advanced prominently gastric OGJA. Findings from a review of these studies33 showed a moderate improvement in 5-year overall survival of only 3–5% after adjuvant chemotherapy.33 However, most of the chemotherapeutic regimens used in these studies are now regarded as suboptimum. Sakuramoto and colleagues34 examined the adjuvant efficacy of single-agent S-1 (active combination of tegafur, gimeracil, and oteracil) compared with surgery alone, in a study of 1059 patients with stage II or III disease after having potentially curative D2 gastrectomy. After a 3-year follow-up and rare grade 3/4 toxic effects, overall survival was favoured in the group receiving S-1 over surgery alone (81·1% vs 70·1%, p=0·0015), as was relapse-free survival (72·2% vs 60·1%, p=0·0001).34 An Italian trial35 did not show an overall survival benefit for adjuvant chemotherapy (epirubicin, etoposide, fluorouracil, and folinic acid). However, the subgroup of patients with positive lymph nodes seemed to show some survival advantage. In a meta-analysis36 including an oral fluoropyrimidine regimen and more than 3809 patients with advanced disease, a pooled hazard ratio for overall survival of 0·78 (95% CI 0·71–0·85) was noted in favour of chemotherapy after radical surgery. Subgroup analyses showed that the advantage of chemotherapy was not affected by the depth of tumour infiltration, status of lymph-node metastasis, type of lymphadenectomy, geographical distribution of patients, or route of drug administration. However, selected oral fluoropyrimidines were beneficial compared with intravenous agents.36 Japanese patients have higher postoperative survival rates than do those in European 299

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Panel: Recommendations for surgical treatment of oesophagogastric junction adenocarcinoma Type I Resection: en-bloc superior polar oesogastrectomy via the transthoracic approach is recommended. If there is any contraindication against thoracotomy, or a high operating risk, a transhiatal oesophagectomy with lower mediastinectomy is an alternative. Lymphadenectomy: in the case of a transthoracic approach, extended two-field lymphadenectomy (abdominal and thoracic) should be done. In the event of a transhiatal approach, two-field lymphadenectomy should be done via the transhiatal surgical approach with a lower mediastinectomy. Type II Resection: two procedures are possible. Either total gastrectomy with partial oesophagectomy via the abdominal approach, or superior polar oesogastrectomy via the transthoracic or transhiatal approach. Left thoracophrenolaparotomy is not recommended. Lymphadenectomy: in the event of a transhiatal approach, two-field lymphadenectomy should be done via the hiatus with a lower mediastinectomy. For a transthoracic approach, extended two-field lymphadenectomy (abdominal and thoracic) should be done. Type III Resection and lymphadenectomy: the rules are the same as for gastric cancer. Total gastrectomy is recommended with, if necessary, an expansion of en-bloc resection to the nearby organs to achieve an R0 resection. Left thoracophrenolaparatomy is not recommended. In terms of lymphadenectomy, as for gastric cancers, D2 dissection without distal splenopancreatectomy is recommended.

countries and the USA.36 Thus, adjuvant chemotherapy has an acceptable associated morbidity, but a small survival benefit in resectable OGJA. However, this benefit is more pronounced in Japanese patients with an S-1agent oral regimen than it is in patients from other developed countries.

Preoperative chemotherapy versus surgery alone Results from five phase 3 randomised trials that included mainly or exclusively patients with OGJA are available. In the US Intergroup (INT)-0113 study,37 440 patients with oesophageal carcinoma—of whom 54% had OGJA—were randomly assigned to surgery alone or three cycles of preoperative chemotherapy and two cycles of postoperative chemotherapy (fluorouracil and cisplatin). The number of R0 and R1 resections was the same between the two treatment groups. After 55 months of follow-up, no difference in survival was noted between the two groups. In the preoperative chemotherapy group, 20% of patients did not have any surgical resection, compared with 4% in the surgery group. This difference could be due to an extension of the time before surgery that is linked with acute toxicity or early progression of disease. A study by the UK Medical Research Council16 investigated preoperative chemotherapy, consisting of two cycles of fluorouacil and cisplatin, in 802 patients, 66% of whom had prominently oesophageal OGJA.38 The doses per cycle of cisplatin and fluorouracil were lower than they were in the US INT-0113 study,37 Rates of R0 300

and R1 resection were significantly higher in the preoperative chemotherapy group than they were in the surgery-alone group (60% vs 54%, p<0·001). The updated data, with 6·1 years of follow-up, showed a long-lasting benefit in terms of the median survival (16·8 vs 13·3 months, p=0·03) and an increase in 5-year overall survival of 6% for the chemotherapy group, with no difference in the rate of perioperative death or postoperative complications.38 A small, randomised trial in gastric cancer, prematurely stopped due to low accrual, which compared neoadjuvant chemotherapy (fluorouracil, methotrexate, and doxorubicin; n=29) with surgery alone (n=30), suggested poor efficacy of the chemotherapy regimen: the R0 resection rate was 62% in the surgery-alone group compared with 56% in the chemotherapy group.39,40 The UK MAGIC study41 tested the efficacy of three cycles of neoadjuvant treatment (cisplatin, fluorouracil, and epirubicine) followed by surgery and then three other cycles, with surgery alone in 503 patients with oesophageal or gastric adenocarcinoma of stage II and above, 26% of whom had OGJA. The proportion of patients with curative resection was larger in the combined chemotherapy group than it was in the surgeryalone group (79% vs 69%, p=0·018). With a median follow-up of 49 months, a significant improvement in overall survival (36% vs 23%, p=0·009) and disease-free survival (30% vs 17%, p<0·001) was also noted in the combined chemotherapy group compared with the surgery-alone group. A French trial,42 which included 224 patients with adenocarcinoma (75% with OGJA), randomly assigned patients to surgery alone or perioperative chemotherapy groups (two or three cycles of cisplatin and fluorouracil followed by surgery, then one to four cycles of chemotherapy).42 The rates of R0 resection were 74% and 87% in the two groups, respectively (p=0·04). After a median follow-up of 5·7 years, 5-year overall survival was 38% in the perioperative chemotherapy group compared with 24% in the surgery-alone group (p=0·021). A meta-analysis, based on individual data from patients with oesophageal OGJA, showed benefits in overall survival of around 7% after 2 years for preoperative chemotherapy,43 confirming the findings of another metaanalysis on oesophageal adenocarcinomas.44 The rate of metastatic recurrence was reduced by preoperative chemotherapy (42% vs 56% in the surgery-alone group), whereas the rate of local control of the disease remained identical at around 25%. The continuation of treatment with chemotherapy in OGJA, guided by metabolic response as shown by PET, has been assessed in a phase 2 study.45 After induction chemotherapy with fluorouracil and cisplatin, 119 patients with OGJA type I or II had an early PET scan after 2 weeks of treatment. Metabolic responders continued chemotherapy for 12 weeks before surgery, whereas nonresponders underwent immediate surgical resection. After www.thelancet.com/oncology Vol 12 March 2011

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A

B

C

D

Figure 4: Schematic representation of recommended extent of surgical resection for oesophagogastric junction adenocarcinomas Type I (A; subtotal oesophagectomy with superior polar gastrectomy), type II (subtotal oesophagectomy with superior polar gastrectomy [B] or total gastrectomy with inferior oesophagectomy [C]), and type III (D; total gastrectomy). Blue region is tumour site.

a median follow-up of 2·3 years (IQR 1·7–3·0), the median overall survival was not reached in metabolic responders, but was 25·8 months (19·4–32·2) in non-responders (p=0·015). Median event-free survival was 29·7 months in metabolic responders compared with 14·1 months in nonresponders (p=0·002). On the basis of these results, a tailored PET-guided treatment algorithm is being incorporated into some studies. Thus, perioperative chemotherapy allows a significant survival benefit at 5 years for locally advanced resectable OGJA, with an acceptable toxic-effects profile. The use of PET for early response assessment remains investigational and the optimum treatment strategy for non-responders is unknown.

Preoperative chemoradiotherapy versus surgery alone Radiotherapy in the neoadjuvant setting has been proposed for optimisation of locoregional tumour control. Preoperative chemoradiotherapy has several advantages. First, the location of the primary cancer is known more precisely, which aids with planning of more accurate and effective radiation fields. Second, the preoperative approach can allow substantial time to observe high-risk patients for future growth of advanced cancers or metastases. Of the ten controlled phase 3 studies that have been done, four46–49 mainly or exclusively included adenocarcinomas, which were mostly oesophageal entities. Of the two studies that included a small number of patients, mainly with lower oesophagus and OGJA tumours,46,47 only one showed any benefit of chemoradiotherapy in terms of survival.46 However, 5-year survival in the surgery-alone group was much lower than that normally reported in the published work.3,5 www.thelancet.com/oncology Vol 12 March 2011

An Australian study,48 which included 256 patients, 62% of whom had junctional adenocarcinoma, showed a higher rate of tumour sterilisation in squamous-cell carcinoma (26·3%) than in adenocarcinoma (9%). Survival did not differ between the two groups, which included patients who were assigned either preoperative chemoradiotherapy followed by surgery or surgery alone. More recently, the Cancer and Leukemia Group B (CALGB) 9781 study49 randomly assigned 56 patients to receive chemoradiotherapy (50·4 Gy with cisplatin and fluorouracil) followed by surgery, or surgery alone. 42 (75%) patients had stage I–III OGJA. After a median follow-up of 6 years, 5-year overall survival was significantly better in the preoperative chemoradiotherapy group than it was in the surgery-alone group (39% vs 16%, p<0·008). The rate of complete histological response was 40%. This study involved low numbers, which is controversial because 500 patients needed to be included to show a statistically significant difference, and this threshold was not reached due to poor accrual. A recent meta-analysis comparing preoperative chemoradiotherapy with surgery alone, based on individual data, included 1210 patients (32·4% with OGJA, mainly oesophageal) and identified an overall survival benefit from preoperative chemoradiotherapy compared with surgery alone (24·7% vs 18·2% after 5 years—ie, an absolute benefit of 6·5%).50 The rate of R0 resection was significantly increased in the chemoradiotherapy group (hazard ratio [HR] 0·56, 95% CI 0·42–0·74, p<0·0001) and did not increase postoperative mortality. Two recent phase III trials, which are only published in abstract form, provide arguments for a tailored approach with neoadjuvant chemoradiotherapy. The CROSS trial51 301

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showed a significant improvement of median overall survival of neoadjuvant chemoradiotherapy followed by surgery compared with surgery alone (49 vs 26 months, p=0·011) in 363 patients (75·2% OGJA) with locally advanced tumours. However, the FFCD 9901 trial,52 testing for the first time the effect of neoadjuvant chemoradiotherapy in patients with only stage I or II tumours (29·2% OGJA), did not show any survival benefit with neaodjuvant chemoradiotherapy compared with surgery alone (median survivals of 31·8 vs 43·8 months, respectively; p=0·66), with a higher postoperative mortality in the combined group (7·3% vs 1·1%, respectively; p=0·054). Neoadjuvant chemoradiotherapy has, therefore, shown interesting results regarding R0 resection and survival in locally advanced OGJA that has invaded mainly the oesophageal region. The benefit of this strategy, although based on low-level data, seems to be higher when compared with neoadjuvant chemotherapy for prominently oesophageal tumours.

Postoperative chemoradiotherapy versus surgery alone Because the rate of locoregional relapse of gastric adenocarcinoma and OGJA after surgery alone is high, additional treatment strategies have been investigated. A randomised three-arm study, which included 436 patients who had undergone surgery involving gastrectomy for an adenocarcinoma—20% of which were OGJA—was able to compare simple postoperative surveillance, concomitant locoregional radiotherapy of 45 Gy, and postoperative chemotherapy. The rate of locoregional relapse was 57% with surveillance, 34% for radiotherapy, and 41% for chemotherapy. 5-year overall survivals were 20%, 12%, 19%, respectively. Therefore, no benefit from adjuvant treatment was shown.53 The randomised INT-0116 study54 compared surveillance with adjuvant chemoradiotherapy according to the Macdonald regimen in 556 patients with gastric cancer, who had a stage IB–IV non-metastatic adenocarcinoma and who had undergone surgery, mostly with suboptimum lymphadenectomy. Median survival was 35 months in the adjuvant treatment group compared with 26 months in the surveillance group (p=0·005). The absolute benefit on the overall survival rate was 11% after 2 years. An update of the results, with median follow-up of more than 10 years, showed that this difference was maintained in terms of overall survival (HR 1·32, p=0·004) and relapse-free survival (HR 1·51, p<0·001).55 Park and colleagues56 investigated a similar protocol in 290 patients, all of whom were curatively resected with extensive D2 lymph-node dissection. After a median follow-up of 49 months, 43% of patients relapsed, with 67% local and 36% distant relapses. 5-year overall survival was 60% and relapse-free survival was 57%. Rates of survival might seem better in this study than they did in the INT 0116 trial54 because of the higher proportion of patients that completed treatment as planned and the more extensive lymph-node dissection leading to a lower risk of residual positive nodes and optimum staging. 302

An ongoing trial, CALGB 80101,7 is assessing a chemotherapy regimen of epirubicin, cisplatin, and fluorouracil before and after infusional fluorouracil with radiotherapy in a postoperative setting, compared with a control group of postoperative bolus fluorouracil and folinic acid given before and after infusional fluorouracil with radiotherapy. Furthermore, a Dutch trial, investigating whether chemoradiotherapy after preoperative chemotherapy and adequate (D1+) surgery leads to improved survival in comparison with postoperative chemotherapy in resectable gastric cancer, is in progress.58 Adjuvant chemoradiotherapy seems to be a reasonable treatment option for OGJA tumours that have developed mainly in the gastric region in the case of inadequate surgery, a high risk of relapse, or both. The optimum chemotherapy regimen is still under investigation.

Preoperative chemoradiotherapy versus preoperative chemotherapy A randomised trial compared induction chemotherapy followed by preoperative chemoradiotherapy with preoperative chemotherapy alone in 119 patients with OGJA classified as T3–T4Nx.59 The first chemotherapy consisted of two or three cycles of cisplatin, fluorouracil, and folinic acid and the chemoradiotherapy-associated irradiation was 30 Gy over 3 weeks with concomitant chemotherapy with cisplatin and etoposide. Of the 354 patients initially scheduled, 119 patients were included during 5 years. The rate of resection R0 was identical in both groups. After a follow-up period of 45·6 months, the results were in favour of preoperative chemoradiotherapy with higher rates of complete histological response (10·2% vs 2% in the preoperative chemotherapy-alone group, p=0·03). The rate of local control was improved by 18% with preoperative chemoradiotherapy compared with preoperative chemotherapy (mortality rates of 10·2% vs 3·8%), highlighting the toxicity of combination chemotherapy followed by chemoradiation. Thus, neoadjuvant chemoradiotherapy after induction chemotherapy before surgery is a promising approach, but comes with the price of increased toxic effects, which encourages the further validation of this combination in new trials.

Preoperative treatment or postoperative treatment? Preoperative chemoradiotherapy has become a standard in the USA for tumours that have developed on the oesophageal side, with a moderate benefit and a non-significant increase in postoperative morbidity.16,44,46,49 Postoperative chemoradiotherapy, according to the Macdonald regimen in the INT 0116 study,54 is also a standard in the USA for patients with gastric adenocarcinoma or OGJA.55 In Europe, perioperative chemotherapy according to the MAGIC protocol41 is standard for prominently gastric OGJA, because of the increase in overall survival of 13% after 5 years and an acceptable toxicity profile.41 Because of the toxic effects of www.thelancet.com/oncology Vol 12 March 2011

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adjuvant chemoradiotherapy, it is more likely to be proposed in Europe for prominently gastric OGJA in the presence of unfavourable prognostic factors (T3/T4, N2–N3, extranodal involvement, or incomplete resection). So, is there a single therapeutic standard to consider? In the MAGIC study,41 tumours were more frequently locally advanced (62% at stage T3 or T4, p=0·009) with a higher rate of lymph-node invasion (29% of cases N2N3, p=0·01) in the preoperative treatment group than in the surgeryalone group. Furthermore, surgery could be carried out in 87·6% of patients (often delayed) in the preoperative treatment group, whereas 95% of patients in the surgeryalone group underwent surgery. However, the per-protocol analysis in the MAGIC trial41 showed that the R0 resection rate was significantly higher in the preoperative chemotherapy group than it was in the surgery-alone group (79% vs 70%, p=0·03), with this benefit disappearing in an intention-to-treat analysis (68% vs 66%, p=0·64). Postoperative chemotherapy could only be done for half the patients, mainly because of progression or early death (36%), a surgical contraindication (16%), or a postoperative complication (10%). Additionally, the MAGIC study41 included patients with resectable tumour, whereas the INT 0116 study54 was directed at patients who had R0 surgery. Finally, these two studies showed an absolute benefit in overall survival of 8% for the MAGIC study41 and 6% for the INT 0116 study,54 although a direct comparison of the findings between these two studies is not possible, because the populations of patients were different. The choice between the neoadjuvant and adjuvant setting can be thought of as the choice between two inconveniences: to overtreat some patients with a preoperative approach, by treating tumours with a good prognosis, or to undertreat some patients by choosing postoperative chemoradiotherapy with a high risk of recurrence, but poor general and nutritional status after surgery. Results from the German trial59 suggest that neoadjuvant chemoradiotherapy after induction chemotherapy and before surgery might be a promising approach.

Exclusive chemoradiotherapy There is no place for exclusive chemoradiotherapy in operable patients with OGJA based on results from two randomised, phase 3 trials that included mostly patients with oesophageal squamous-cell carcinoma.60,61 In nonoperable patients, exclusive chemoradiotherapy should be proposed from a curative perspective.62

Adjuvant intraperitoneal chemotherapy A meta-analysis pooled studies in which patients with gastric adenocarcinoma or OGJA were randomly assigned to receive surgery with intraperitoneal chemotherapy versus surgery alone.63 A significant improvement in overall survival was associated with hyperthermic intraoperative intraperitoneal chemotherapy alone (HR 0·60, 95% CI 0·43–0·83, p=0·002) or hyperthermic intraoperative intraperitoneal chemotherapy combined www.thelancet.com/oncology Vol 12 March 2011

with early postoperative intraperitoneal chemotherapy (0·45, 0·29–0·68, p=0·0002). This meta-analysis suggests a role of intraperitoneal chemotherapy as an adjuvant treatment for gastric cancer and OGJA. Further clarification of the effectiveness and safety of this treatment is needed.

New horizons in treatment of resectable OGJA To optimise the treatment of resectable locally advanced OGJA, the following points need to be resolved: the preferred endoscopic treatment for tumoural and Barrett’s ablation; the optimum surgical approach for Siewert type II tumours; the appropriate extent of lymphadenectomy; whether extension of surgical resection can be modified after neoadjuvant treatment; how to decrease morbidity and mortality with a minimally invasive approach; identification of an effective chemotherapy regimen; definition of the optimum treatment regimen, with neoadjuvant or adjuvant treatment, or both; and the role and place of radiotherapy. Promising results with oxaliplatin, irinotecan, docetaxel, and capecitabine have been obtained in randomised trials enrolling patients with advanced or metastatic cancer.64,65 Based on the optimistic view that the use of multiple targeted therapies will improve results, various phase 1, 2, and 3 trials are underway, including those testing inhibitors for epidermal growth factor receptors, antibodies to the HER2 receptor and vascular endothelial growth factor ligand, and other new drugs acting on intracellular signalling pathways. A large, randomised trial will assess the association between bevacizumab and the epirubicin, cisplatin, and fluorouracil chemotherapy regimen, substituting fluorouacil with capecitabine in a perioperative setting and comparing it to chemotherapy with epirubicin, cisplatin, and fluorouracil alone.66 The effects of radiotherapy in resectable OGJA have yet to be determined, with assessment of the balance of benefit to risk, the optimum place in a neoadjuvant or adjuvant setting, the optimum associated chemotherapy regimen, and whether any radiation escalation by hyperfractionation or acceleration can improve local control, while maintaining a similar toxicity profile.

Conclusion On the basis of the data collected and discussed in this Review, we propose the following guidelines for the treatment of OGJA. For superficial tumours, endoscopic mucosal resection could be proposed for T1m1 to sm1 OGJA if the tumour is well-differentiated, not depressed, and smaller than 2 cm. In the case of invasive lesions on the resected specimen (sm2 or sm3), because of the high risk of lymph-node involvement, curative surgery is needed in operable patients and exclusive chemoradiotherapy in non-operable patients. Treatment of the underlying premalignant disorder should be proposed in combination with the tumour ablation. For T1–2 N0 lesions, oesophagectomy with lymphadenectomy is the standard treatment for type I OGJA and gastrectomy with 303

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Search strategy and selection criteria 7

We searched Medline, Cancerlit, Embase, and references of relevant articles with the search terms “randomised trials”, “junction adenocarcinoma”, “treatment”, “surgery“, “chemotherapy”, “radiotherapy”, and “chemoradiotherapy” for papers published in English between January, 2000, and May, 2010. Data related to oesophageal or gastric cancers were included only if a substantial portion was concerned with treatment of oesophagogastric junction adenocarcinoma. Prospective or retrospective non-randomised studies were only considered when methodology was relevant and a high number of patients were included. Abstracts and reports from meetings were included only when they were directly related to previously indexed randomised trials and gave useful, new information regarding treatment of oesophagogastric junction adenocarcinoma.

lymphadenectomy for type III OGJA. For type II OGJA, superior polar oesogastrectomy or total oesogastrectomy approaches are both possible if an R0 resection is achievable. For T1–4 N1–3 lesions, preoperative or perioperative chemotherapy are valid approaches for type I or II OGJA, but preoperative chemoradiotherapy should be discussed, especially for locally advanced tumours that have developed on the oesophageal side. For type III OGJA, perioperative chemotherapy or postoperative chemoradiotherapy are valid options, with the latter being proposed in the presence of unfavourable postoperative prognostic factors in patients without preoperative treatment. The same surgical guidelines as described previously need to be applied, with a benefit gained from extending resection to nearby organs for curative purposes for locally advanced tumours. In non-operable patients, exclusive chemoradiotherapy should be proposed in a curative setting. Contributors CM, GP, NB, and CG collected data. CM and GP did the data analysis, and CM wrote the report. All authors contributed to discussion and approved the final version Conflicts of interest The authors declared no conflicts of interest.

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