Council Adjuvant Gastric Infusional Chemotherapy Research Articles

Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma – A comparison of the FLOT and ‘MAGIC’ regimens

BackgroundPeri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates. MethodsCohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas’ Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells. ResultsPatients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50–0.94) and disease-free survival (HR = 0.75, 95% CI 0.58–0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups. ConclusionsPatients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.

The Landmark Series: Multimodal Therapy for Esophageal Cancer.

Esophagectomy is the mainstay of treatment for patients with resectable esophageal cancer, and chemotherapy and chemoradiation have become essential adjuncts to improve survival. Controversy remains regarding the optimal perioperative therapy. This review focuses on three landmark, randomized, controlled trials that have greatly influenced esophageal cancer management and established chemotherapy and chemoradiotherapy as standard of care: Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial (MAGIC); The United Kingdom Medical Research Council Esophageal Cancer Trial (OEO2); and Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS). The findings from these landmark studies are reviewed and summarized. Chemotherapy regimens are heterogeneous but centered around platinum-based therapy and should be included in the management for all appropriate patients. Ongoing and future studies will further delineate the roles of various chemo- and chemoradiotherapy regimens and also will investigate the promising area of immunotherapy in the treatment of esophageal cancer.

Treatment in resectable non-metastatic adenocarcinoma of stomach: Changing paradigms.

Adjuvant treatment in gastric adenocarcinoma has been a challenge for the treating specialists, and despite several trials, a clear consensus is yet to be defined. The higher propensity for lymph nodal involvement and locoregional recurrences led to the hypothesis that locoregional and systemic treatments need to be equally aggressive to achieve better outcomes in the management of gastric adenocarcinoma. Regional, ethnic, and biological differences between the Eastern and Western population are also found to reflect in the tumor behavior and its response to treatment. The MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy), Intergroup 0116, ACTS-GC (Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer), CLASSIC (Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer), ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer), and the recently published CRITICS (Chemoradiotherapy after Induction Chemotherapy in Cancer of the Stomach) trials were a few of the randomized controlled trials that tried to give a clearer perspective of this tumor, though it still remains a dilemma. A study incorporating the tumor and demographic factors along with the availability of skilled talent and resources might generate an answer.

A seven-Gene Signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial

BackgroundFollowing neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse. Patients and methodsThe Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n = 202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort. ResultsRegression and clustering analysis of MAGIC patients defined a seven-Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P < 0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P = 0.02; HR 3.6 in high-risk group, P = 0.0002), and not prognostic in surgery only patients (n = 118; log rank P = 0.2). A validation cohort independently confirmed these findings. ConclusionsThese results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials.

Mismatch Repair Deficiency, Microsatellite Instability, and Survival

Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown. To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed. Interaction between MMRD and MSI status and overall survival (OS). Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4%)] and 20 with high MSI [median age, 66 years; 14 males (70.0%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95% CI, 16.7-27.8 months; hazard ratio, 0.42; 95% CI, 0.15-1.15; P = .09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95% CI, 15.4-35.2 months; hazard ratio, 2.18; 95% CI, 1.08-4.42; P = .03). In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy.

Current adjuvant treatment modalities for gastric cancer: From history to the future.

The discrepancy between the surgical technique and the type of adjuvant chemotherapy used in clinical trials and patient outcomes in terms of overall survival rates has led to the generation of different adjuvant treatment protocols in distinct parts of the world. The adjuvant treatment recommendation is generally chemoradiotherapy in the United States, perioperative chemotherapy in the United Kingdom and parts of Europe, and chemotherapy in Asia. These options mainly rely on the United States Intergroup-0116, United Kingdom British Medical Research Council Adjuvant Gastric Infusional Chemotherapy, and the Asian Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer and Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer trials. However, the benefits were evident for only certain patients, which were not very homogeneous regarding the type of surgery, chemotherapy regimens, and stage of disease. Whether the dissimilarities in survival are attributable to surgical technique or intrinsic biological differences is a subject of debate. Regardless of the extent of surgery, multimodal therapy may offer modest survival advantage at least for diseases with lymph node involvement. Moreover, in the era of individualized treatment for most of the other cancer types, identification of special subgroups comprising those who will derive more or no benefit from adjuvant therapy merits further investigation. The aim of this review is to reveal the historical evolution and future reflections of adjuvant treatment modalities for resected gastric cancer patients.

Radiotherapy patterns of care in gastric adenocarcinoma: a single institution experience.

Gastric adenocarcinoma (GAC) is one of the most commonly diagnosed cancers worldwide. Two standard approaches for treatment of resectable GAC include adjuvant 5-fluorouracil-based chemoradiotherapy [per Intergroup 0116 (INT-0116) trial and perioperative epirubicin, cisplatin, fluorouracil (ECF) chemotherapy per Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial]. Controversy remains regarding the most appropriate treatment strategy to decrease recurrence rates and improve survival following surgery. The purpose of this study was to analyze how patterns of care for patients with GAC treated at Emory University Hospital changed following publication of the MAGIC trial in 2006. We analyzed a prospectively maintained database of 150 patients who underwent resection for GAC between December 2000 and June 2013. Patients were divided into two cohorts, Early [2000-2006] and late [2007-2013]. The primary objective was to compare the number of patients assigned to adjuvant chemoradiotherapy (aCRT) vs. perioperative chemotherapy (PC) throughout the study period and secondarily assess for recurrence patterns and survival outcomes for patients assigned to those two strategies. Between 2000 and 2013, 124 patients received adjuvant therapy for GAC. Fifty-four patients were treated with PC and 70 patients with aCRT. The early cohort included 56 patients, and the late cohort included 94 patients. There was no statistical difference in the number of patients receiving aCRT between the Early and Late cohorts [n=23 (50%) vs. 35 (38%) respectively, P=0.21]. PC increased from 2 patients (3.6%) in the Early cohort to 32 patients (34%) in the Late cohort (P<0.001). Four-year overall survival (OS) was 32.6% for the Early cohort and 68.8% for the Late cohort (P=0.010). Overall recurrence rate was 25.3% with no significant difference in rates of recurrence seen between the Early and Late cohorts. PC has become more prevalent in patients treated at Emory following publication of the MAGIC trial in 2006. OS, but not recurrence rates, has also improved since publication. Although improved survival is suggestive of improved care, the question of optimal treatment regimen remains open. Further prospective comparisons of PC and aCRT are needed to identify patient and disease parameters that may guide therapy selection.

Trends in the use of evidence-based therapy for resectable gastric cancer.

Two pivotal randomized controlled trials (RCTs), the Intergroup (INT-0116) and Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trials, demonstrated a survival benefit of multimodality therapy in patients with resectable gastric cancer. The purpose of this study was to determine utilization rates of these treatment regimens in the United States and to identify factors associated with receipt of evidence-based care. We performed a retrospective cohort study of patients with Stage IB-IV (M0) gastric adenocarcinoma who underwent resection from 1991 to 2009 using the linked SEER-Medicare database. Only 19.1% of patients received post-operative chemoradiation therapy (CRT), and 1.9% received peri-operative chemotherapy; most patients underwent surgery alone (60.9%). Patients with more advanced stage, younger age, and fewer comorbidities were more likely to receive evidence-based care. We found no association between National Cancer Institute (NCI) designation and delivery of multimodality therapy. However, patients who underwent medical oncology consultation were much more likely to receive evidence-based treatment (OR 3.10, 95% CI 2.35-4.09). Rates of peri-operative chemotherapy and post-operative CRT in patients with resected gastric cancer remain remarkably low, despite high-quality RCT evidence demonstrating their benefit. Furthermore, NCI designation does not appear to be associated with administration of evidence-based treatment.

Multimodality management of resectable gastric cancer: A review.

Adenocarcinoma of the stomach carries a poor prognosis and is the second most common cause of cancer death worldwide. It is recommended that surgical resection with a D1 or a modified D2 gastrectomy (with at least 15 lymph nodes removed for examination) be performed in the United States, though D2 lymphadenectomies should be performed at experienced centers. A D2 lymphadenectomy is the recommended procedure in Asia. Although surgical resection is considered the definitive treatment, rates of recurrences are high, necessitating the need for neoadjuvant or adjuvant therapy. This review article aims to outline and summarize some of the pivotal trials that have defined optimal treatment options for non-metastatic non-cardia gastric cancer. Some of the most notable trials include the INT-0116 trial, which established a benefit in concurrent chemoradiation and adjuvant chemotherapy. This was again confirmed in the ARTIST trial, especially in patients with nodal involvement. Later, the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial provided evidence for the use of perioperative chemotherapy. Targeted agents such as ramucirumab and trastuzumab are also being investigated for use in locally advanced gastric cancers after demonstrating a benefit in the metastatic setting. Given the poor response rate of this difficult disease to various treatment modalities, numerous studies are currently ongoing in an attempt to define a more effective therapy, some of which are briefly introduced in this review as well.

Neoadjuvant or adjuvant therapy for resectable gastric cancer: a systematic review and practice guideline for North America

Gastric cancer is a global health problem accounting for 10% of all new cancer cases and 12% of all cancer deaths worldwide. Many clinical trials and meta-analyses have explored the value of neoadjuvant or adjuvant chemotherapy and radiation therapy in gastric cancer; however, these studies have produced conflicting results. The purpose of this guidance document was to determine whether patients with resectable gastric cancer should receive neoadjuvant or adjuvant therapy in addition to surgery. Outcomes of interest were overall survival, disease-free survival, and adverse events. A systematic review was undertaken to inform recommendations regarding neoadjuvant and adjuvant therapy in resectable gastric cancer in Ontario, Canada. MEDLINE and EMBASE databases, as well as American Society of Clinical Oncology (ASCO) annual meeting proceedings and American Society for Therapeutic Radiology and Oncology (ASTRO) proceedings were systematically searched from 2002 to 2010. Oral fluoropyrimidine trials were excluded owing to the unavailability of these agents in North America. Overall, 22 randomized controlled trials (RCTs), 13 meta-analyses, and two secondary analyses were included. The systematic review informed the development of a clinical practice guideline with the following recommendations. Postoperative 5-fluorouracil-based chemoradiotherapy based on the Macdonald approach or perioperative ECF (epirubicin, cisplatin, fluorouracil) chemotherapy based on the Cunningham/MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) approach are both acceptable standards of care in North America. Choice of treatment should be made on a case-by-case basis. Adjuvant chemotherapy is a reasonable option for those patients for whom the Macdonald and MAGIC protocols are contraindicated. All patients with resectable gastric cancer should undergo a pretreatment multidisciplinary assessment to determine the best plan of care. Overall survival in patients with resectable gastric cancer is significantly improved with the use of either postoperative chemoradiation (Macdonald approach) or perioperative ECF (MAGIC protocol).

Limited Advantages of Intensity-Modulated Radiotherapy Over 3D Conformal Radiation Therapy in the Adjuvant Management of Gastric Cancer

Although chemoradiotherapy was considered the standard adjuvant treatment for gastric cancer, a recent Phase III trial (Medical Research Council Adjuvant Gastric Infusional Chemotherapy [MAGIC]) did not include radiotherapy in the randomization scheme because it was considered expendable. Given radiotherapy's potential, efforts needed to be made to optimize its use for treating gastric cancer. We assessed whether intensity-modulated radiotherapy (IMRT) could improve upon our published results in patients treated with three-dimensional (3D) conformal therapy. Fourteen patients with adenocarcinoma of the stomach were treated with adjuvant chemoradiotherapy using a noncoplanar four-field arrangement. Subsequently, a nine-field IMRT plan was designed using a CMS Xio IMRT version 4.3.3 module. Two IMRT beam arrangements were evaluated: beam arrangement 1 consisted of gantry angles of 0 degrees , 53 degrees , 107 degrees , 158 degrees , 204 degrees , 255 degrees , and 306 degrees . Beam arrangement 2 consisted of gantry angles of 30 degrees , 90 degrees , 315 degrees , and 345 degrees ; a gantry angle of 320 degrees /couch, 30 degrees ; and a gantry angle of 35 degrees /couch, 312 degrees . Both the target volume coverage and the dose deposition in adjacent critical organs were assessed in the plans. Dose-volume histograms were generated for the clinical target volume, kidneys, spine, and liver. Comparison of the clinical target volumes revealed satisfactory coverage by the 95% isodose envelope using either IMRT or 3D conformal therapy. However, IMRT was only marginally better than 3D conformal therapy at protecting the spine and kidneys from radiation. IMRT confers only a marginal benefit in the adjuvant treatment of gastric cancer and should be used only in the small subset of patients with risk factors for kidney disease or those with a preexisting nephropathy.

Transition in Biology and Philosophy in the Treatment of Gastroesophageal Junction Adenocarcinoma

Transition in Biology and Philosophy in the Treatment of Gastroesophageal Junction Adenocarcinoma

Neoadjuvant treatment in upper gastrointestinal adenocarcinomas: new paradigms from old concepts?

Despite a decline in the incidence of upper gastrointestinal adenocarcinomas in North America and western Europe during the past century, treatment remains a challenging problem for oncologists. The poor outcome associated with surgical resection with curative intent has generated intensive investigation of combined modality treatment approaches including systemic chemotherapy to prevent recurrences and improve overall mortality. This article reviews data on neoadjuvant and perioperative treatment modalities for upper gastrointestinal adenocarcinomas. Postoperative chemoradiation is favored in the USA for good performance status patients with resected, high-risk gastric or gastroesophageal junction carcinoma (more stage IA). More recently, the UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) and Fédération Nationale des Centres de Lutte Contre le Cancer-Fédération Francophone de Cancérologie Digestive trials results, showing survival benefit with perioperative chemotherapy in operable gastric and lower esophageal cancers, have had an impact on the treatment practice in Europe. Novel strategies, involving induction with chemotherapy followed by preoperative chemoradiation, addition of targeted therapies to perioperative chemotherapy or use of new cytotoxic regimens are under evaluation to improve current standards and try to tailor therapeutic strategies.

Neo-adjuvant and adjuvant chemotherapy of gastric cancer

Gastric cancer is still a major health problem and a leading cause of cancer mortality despite a worldwide decline in incidence. Surgery is the primary curative treatment of locoregional gastric cancer. In Western countries, however, at the time of resection, most patients are expected to have regional lymph node involvement with poor prognostic implications. To improve these results, different trials have been carried out in the adjuvant or neo-adjuvant setting. Many phase III trials of adjuvant therapy have been conducted; however, postoperative treatment modalities have not proven to be superior to postsurgical observation alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed. On the contrary, neo-adjuvant chemotherapy has shown promising results as suggested by the final results of UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial.

Gastroesophageal cancers: web resources

Many stomach and oesophageal cancers are advanced when they are diagnosed making the treatment palliative and the prognosis poor. The effective relief of symptoms that restrict enjoyment of the physical, psychological and social elements of life, such as eating and drinking is paramount. Nevertheless, research into the causes and treatment of this significant cause of cancer morbidity and mortality continues and a recent report on the addition of a regimen of perioperative chemotherapy before and after surgery for localized respectable gastric cancer was found to significantly improve survival compared with surgery alone. The researchers report on results from the UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial may be in the July 6 issue of the New England Journal of Medicine.

Adjuvant and Neoadjuvant Therapy for Gastric Carcinoma

Despite its declining incidence, gastric cancer remains one of the leading causes of cancer-related death worldwide. The definitive management of localized gastric cancer has been the center of much international controversy over the years; surgery remains the mainstay, with debate centering on the required extent of lymph node resection. The role of adjuvant chemotherapy has been studied for decades, but because trials have been underpowered, it has been difficult to demonstrate a statistically significant benefit. Recently, four large meta-analyses have been published on adjuvant chemotherapy in gastric cancer. The first three have been criticized for their methodology, but the most recent meta-analysis was well conducted and showed a statistically significant benefit in favor of adjuvant chemotherapy. The heterogeneity of chemotherapy schedules included in this meta-analysis, however, makes it difficult to define the current standard. Randomized trials in the metastatic setting have shown that the combinations of epirubicin, cisplatin, and infusional fluorouracil (ECF) and docetaxel, cisplatin, and fluorouracil (TCF) have demonstrated superiority over other regimens. The role of preoperative chemotherapy is currently under investigation, with results from the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial demonstrating a significant improvement in resectability, progression-free survival, and overall survival with perioperative therapy in patients with operable gastric cancer. Postoperative chemoradiotherapy has also been adopted as a standard of care in the US following the publication of the results of the Intergroup Study, INT-0116, although there remains debate over the relative benefits of more radical surgery versus the use of radiation with adjuvant treatment. It is clear that adjuvant therapy is now an appropriate addition to surgery, although there are still further questions regarding the optimal protocols.