|Year : 2014 | Volume
| Issue : 4 | Page : 866-870
Epirubicin, oxaliplatin, and capectabine is just as "MAGIC"al as epirubicin, cisplatin, and fluorouracil perioperative chemotherapy for resectable locally advanced gastro-oesophageal cancer
Bhawna Sirohi1, Savio George Barreto2, Ashish Singh1, Swati Batra2, Abhishek Mittra2, Sameer Rastogia1, Mukta Ramadwar3, Nitin Shetty4, Mahesh Goel3, Shailesh V Shrikhande3
1 Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
2 Department of Gastrointestinal and Hepato-Pancreato-Biliary Surgical Oncology, Tata Memorial Centre, Mumbai, India
3 Department of Pathology, Tata Memorial Centre, Mumbai, India
4 Department of Radiodiagnosis, Tata Memorial Centre, Mumbai, India
|Date of Web Publication||9-Jan-2015|
Consultant Medical Oncologist - GI and Breast Cancers, GI Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: The perioperative use of epirubicin, cisplatin, and fluorouracil (ECF) significantly improves outcomes in patients with gastric and gastro-oesophageal (GO) cancers but is cumbersome to administer. Given the equivalence of epirubicin, oxaliplatin, and capectabine (EOX) with ECF in advanced setting, we analyzed the compliance, efficacy, and toxicity of perioperative EOX in resectable but locally advanced cancers.
Methods: This is a retrospective analysis of prospectively maintained database of patients treated between January 2012 and September 2013 at Tata Memorial Centre. Patients were planned to receive 3# of neoadjuvant (NA) and 3# of adjuvant EOX (intravenous epirubicin 50 mg/m 2 D1, oxaliplatin 130 mg/m 2 , on D1, capecitabiine 1250 mg/m 2 D1-21) every 21 days. On completion of NA therapy, patients were planned to undergo gastrectomy and D2 lymphadenectomy.
Results: A total of 99 patients (76% males, median age 51 years) were treated with perioperative EOX. Preoperatively, 93% patients completed EOX. Post-NA chemotherapy, 4 patients progressed, 1 patient died and 94 were taken up for surgery. Of these, 9 were inoperable and 85 patients underwent radical surgery. Of these, 71% (60/85) were able to complete three cycles of adjuvant EOX. The compliance to complete all 6 cycles of perioperative chemotherapy was 64%. Grade 3 and 4 toxicities were comparable to the MAGIC dataset apart from higher number of diarrhea in our patients.
Conclusions: In patients with resectable GO adenocarcinoma, it is possible to deliver the MAGIC-type perioperative chemotherapy with EOX with better compliance, toxicity, and efficacy rates.
方法：回顾性分析2012年1月到2013年9月之间在Tata Memorial中心治疗的患者。患者接受3疗程新辅助（NA）和3疗程辅助EOX（静脉注射表阿霉素50 mg/m2 d1，奥沙利铂130 mg/m2，D1，卡培他滨 1250 mg/m2 D1-21）每21天1疗程。在新辅助治疗后，胃切除和D2淋巴结清扫术。
Keywords: Epirubicin, oxaliplatin, and capectabine, compliance, gastric cancer, treatment
|How to cite this article:|
Sirohi B, Barreto SG, Singh A, Batra S, Mittra A, Rastogia S, Ramadwar M, Shetty N, Goel M, Shrikhande SV. Epirubicin, oxaliplatin, and capectabine is just as "MAGIC"al as epirubicin, cisplatin, and fluorouracil perioperative chemotherapy for resectable locally advanced gastro-oesophageal cancer. J Can Res Ther 2014;10:866-70
|How to cite this URL:|
Sirohi B, Barreto SG, Singh A, Batra S, Mittra A, Rastogia S, Ramadwar M, Shetty N, Goel M, Shrikhande SV. Epirubicin, oxaliplatin, and capectabine is just as "MAGIC"al as epirubicin, cisplatin, and fluorouracil perioperative chemotherapy for resectable locally advanced gastro-oesophageal cancer. J Can Res Ther [serial online] 2014 [cited 2019 Nov 17];10:866-70. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/866/146122
| > Introduction|| |
The improvement in outcomes of patients with gastric cancer, as witnessed by the success of trials adding chemotherapy and/or radiotherapy to surgery in the perioperative and adjuvant settings, ,,, has spawned a paradigm shift in the management of gastric cancer. While surgery remains the main treatment modality for achieving a cure, the focus has now shifted to a unified, multidisciplinary approach in gastric cancer  wherein medical and radiation oncologists are working more closely with surgeons, at a much earlier stage in the treatment plan, so as to increase the number of patients who can be potentially offered a curative resection. This is all being done with a common aim-to improve the long-term survival of gastric cancer.
The MAGIC trial by Cunningham et al.  demonstrated a 13% increase in overall survival with peri-operative chemotherapy compared to surgery alone. Thus, oncologists around the world are steadily considering a change in practice based on these results.  In India, too, we adopted the MAGIC regimen  but found the epirubicin, cisplatin and fluorouracil (ECF) regimen (proposed by the MAGIC trial) cumbersome owing to inherent problems such as higher toxicities  and also difficulties in the need for central venous access. This led us to try out a number of other regimens  based on the literature from other trials (conducted in patients with advanced gastric cancer), including the REAL-2 trial. , The REAL-2 trial  established the epirubicin, oxaliplatin, and capectabine (EOX) regimen (epirubicin, oxaliplatin, and capecitabine) to be noninferior to ECF (administered in the MAGIC trial). The regimen was found to have a favorable toxicity profile in our patients  and is hence increasingly the preferred chemotherapy regimen at our center in the perioperative setting.
The aim of the current study was to analyze the compliance, toxicity, and efficacy of EOX regimen administered as perioperative chemotherapy in patients with resectable gastric and gastro-oesophageal (GO) adenocarcinoma treated at our center.
| > Methods|| |
A retrospective analysis of a prospectively maintained database was performed of patients with resectable gastric and GO cancer treated at the Tata Memorial Centre (tertiary care cancer referral center) with EOX between January 2012 and September 2013. Patients were eligible to receive neoadjuvant (NA) chemotherapy if they had  biopsy proven gastric adenocarcinoma, multidetector-computed tomography scan (chest and abdomen) indicative of tumour stage (≥T3), perigastric fat stranding, with or without nodal metastases, and no evidence of distant metastases.
Patients were planned to receive 3 cycles of NA EOX (intravenous epirubicin 50 mg/m 2 on day 1, oxaliplatin 130 mg/m 2 on day 1, and capecitabiine (Cape) 1250 mg/m 2 from day 1 to 21; cycle repeated every 21 days). On completion of the NA cycles, patients were planned for a radical gastrectomy and D2 lymphadenectomy  which would be followed by 3 cycles of adjuvant EOX. Some patients received Cape-Ox (capecitabine 1700 mg/m 2 day 1-14 in two divided doses and Oxaliplatin 130 mg/m 2 on day 1-21 days) or Cape alone (2000 mg/m 2 day 1-14 q 21 days) due to reasons described below in their treatment pathway.
Re-staging/assessment of response after neoadjuvant chemotherapy
Response to treatment was not recorded by site-specific radiologists, hence the notes were reviewed. Complete response (CR) was defined as disappearance of all baseline lesions, partial response (PR) was labeled marked regression of the baseline lesion, stable disease (SD) was no regression and progressive disease was defined as appearance of new lesions or increase in size of baseline lesions. Recist criteria were not used for staging.  The response was recorded in case files as SD, CR, disease progression (PD), or PR after a joint clinic meeting of the gastrointestinal disease management group.
The data of the present study were collected in the course of common clinical practice and accordingly, the signed informed consent was obtained from each patient for any surgical and clinical procedure.
All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS Inc. IBM.) Inc., version 18.0 for Windows. Nominal data are provided as number (%) and continuous data as median (range).
| > Results|| |
Demography and clinico-pathological parameters
A total of 99 patients, including 75 male (76%) and 24 female patients with a median age of 51 years (range, 30-77) was commenced on NA EOX within the study period. These included 17 patients (17%) with lower esophageal and GO junction and 82 patients (83%) with gastric cancers. The median serum carcinoembryonic antigen levels were 3.69 (range: 0.54-717 ng/ml) while the serum carbohydrate antigen 19-9 (CA: 19-9) levels were 15.32 (range: 0-7309 U/ml). A total of 74 patients (75%) had poorly differentiated adenocarcinomas while 41 patients (41%) had signet ring histology. [Table 1] shows the demography of these patients compared to the MAGIC trial.
|Table 1: Comparison of the demography of patients between the MAGIC trial and the present series|
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Compliance to planned neoadjuvant chemotherapy regimen
92 (93%) of the 99 patients who were commenced on the planned EOX regimen, completed the planned 3 cycles (2 patients received extended NA chemotherapy with 4 and 7 cycles each) while 4 patients and 1 patient received 2 and 1 cycle, respectively. In 1 patient who developed grade 3 fatigue, a 25% dose reduction in cape were needed followed by the remaining two cycles being Cape-Ox. One patient died as a result of chemotherapy-related toxicity after 2 cycles of acute renal failure secondary to grade 4 diarrhea.
Response to NA chemotherapy
Of the 99 patients, response was not assessed in 2 patients (1 died). One patient attained radiologic CR, 57 PR, 35 SD, and 4 patients progressed on NA chemotherapy.
Of the 98 patients, 4 patients were not taken up for surgery owing to PD on imaging. Of the remaining 94 patients who were explored, 85 patients (91%) underwent radical gastrectomy with D2 lymphadenectomy with or without extended resections while 9 patients (9%) were found to be inoperable. The surgical data have been summarized in [Table 2]. Six patients had a complete pathological response (7%) while another 2 patients had scanty residual disease.
|Table 2: Details of the 94 patients who underwent surgery and the comparison with the patient cohort from the perioperative arm of the MAGIC trial|
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79 (93%) of the 85 patients who underwent surgery (surgical mortality - 2 patients: Duodenal stump blow-out and postoperative pancreatitis) received adjuvant chemotherapy. 71 (90%) of the 79 patients were recommended three cycles of EOX - 63 patients were able to receive all 3 cycles, 5 received two cycles, 2 patients received one cycle, and 1 patient was lost to follow-up. 8 patients were treated with adjuvant Cape-Ox or Cape alone in view of either grade 3 or 4 toxicity during NA chemotherapy or the plan was changed to chemo radiotherapy plus Cape-Ox in view of R1 resection (n = 5).
Epirubicin, oxaliplatin, and capectabine-related toxicity
37 patients (37%) developed toxicities in the NA cycles while 21 patients (30%) were found to develop toxicities during the adjuvant cycles. The grade 3/4 toxicities noted in both, NA and adjuvant, cycles are as follows (figures in brackets are from MAGIC data): Diarrhea 14% (2.6-3.6%), mucositis 3% (3.6-4.3%), fatigue 6% (not reported), neuropathy 3% (4%), febrile neutropenia 4% (not reported), palmar plantar erythema (PPE) 6% (1.5-3%), hiccups 4%, nausea and vomiting 7% (6-10%), thrombocytopenia 3% (3%), extravasation 2% (not reported), deep vein thrombosis 2% (not reported), and 1 patients each had acute renal failure, hyponatremic seizures, and elevation in hepatic transaminases.
[Figure 1] shows a schematic representation of the patients planned for EOX at the outset and the number of patients who completed all cycles of planned therapy (including surgery).
|Figure 1: Schematic representation of the patients planned for, and treated with, EOX who completed all cycles of planned therapy (including surgery) (symbols: #-cycle)|
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| > Compliance to all six cycles of chemotherapy|| |
63/99 (63.6%) of patients completed all planned six cycles of peri-operative chemotherapy. 36 patients did not complete all 6 cycles due to following reasons- inoperable (n = 10), plan changed to chemo-radiotherapy in view of R1 resection (n = 5), toxicity (n = 8), progression on adjuvant or NA chemotherapy (n = 5), postoperative complications (n = 2), died postsurgery (n = 2), died postadjuvant or NA chemotherapy (n = 2), patient choice (n = 1), and lost to follow-up (n = 1).
| > Discussion|| |
These data are the largest reported on the perioperative use of EOX and also the first from India for patients with resectable gastric and GO cancer. We show that the perioperative use of EOX has comparable safety and efficacy to ECF.
The two pivotal randomized trials United Kingdom (UK)-MRC MAGIC and the French FNLCC FFCD have established the use of perioperative ECF in UK and Europe with a level IA recommendation given in the ESMO guidelines. ,, Given the need for central venous access for the administration of ECF, the use of perioperative ECX (infusional 5-fluorouracil [5-FU] being replaced with cape) is given a level 4C recommendation. There has been a steady increase in the use of perioperative chemotherapy in resectable, nonmetastatic, locally advanced GO cancers around the world, including India ,,, following the above trials. In the secondary analysis of the REAL-2 study, overall survival was longer in patients who received EOX compared to those patients who received ECF. Hence, we replaced ECF with EOX for peri-operative treatment of resectable gastric and GO cancer patients based on our initial experience with EOX.  The present study was aimed at objectively assessing the compliance, toxicity, and efficacy to EOX - since there are currently no data from India and sparse data from the rest of the world in this setting. , We have compared our results with the MAGIC data.
On comparing our data with the ECF regimen in the MAGIC trial,  we find that the compliance to NA chemotherapy was identical between the two studies with a chemotherapy-related mortality of 1% noted in both studies. Pathological CR were not noted with ECF but were found in 6% of patients in our series. The overall compliance (completion of the planned 6 cycles of chemotherapy) was 63.6% in our study compared to 42% in the MAGIC trial. Given the ease of administration both oxaliplatin and cape compared with cisplatin and infusional 5-FU, there is better compliance with EOX and a manageable toxicity profile.
The patients in our series had higher incidence of Grade 3 and 4 diarrhea and PPE due to the use of Cape but the rest of the toxicities were comparable. Intractable hiccups were seen in 4% of our patients, this has not been reported with the ECF regimen.
All the patients in our study underwent a D2 lymphadenectomy compared to 42% in the MAGIC trial. Results of surgery are better in our series both [Table 2] for morbidity and mortality possibly due to the fact that all patients were operated at a single center with standardized protocols.  These data also show that it is safe to administer perioperative chemotherapy with D2 lymphadenectomy without increasing surgical morbidity or mortality. Most of the data with D2 lymphandenectomy from Asia are on adjuvant chemotherapy. , Patients in our series had significantly worse disease on pathology compared to the MAGIC data (62% vs. 48% T3/T4; 34% vs. 15% N2/N3 disease) which could be due to higher number of patients seen with signet ring histology though these data are not reported in the MAGIC study. [Table 3] shows our experience with perioperative EOX in comparison with the two other studies reported in literature from China and Ireland. ,
|Table 3: Comparison of compliance, toxicity and efficacy profile of EOX in published literature|
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There are limitations to our data. The study is retrospective and the data collection for grade 1 and 2 toxicity is not robust. However, the solid end-points of mortality, efficacy, pathology, surgery, and grade 3 and 4 toxicity are well-captured.
While surgery remains the cornerstone for achieving a cure in gastric cancer, chemotherapy adds to the survival advantage. Similar to pancreatic cancer,  in gastric cancer,  too, completion of the planned chemotherapy cycles is an independent prognostic factor. Mirza et al.  have shown that patients with gastric and GO cancers who completed their planned adjuvant cycles had a significantly better survival than those who only received NA chemotherapy. Thus, a regimen like EOX with a good compliance, toxicity, and efficacy profile presents itself as a formidable choice in the perioperative management of patients with gastric or GO cancers.
| > Conclusions|| |
Our study, the largest cohort of EOX-related compliance, toxicity, and efficacy reported to date, demonstrates a satisfactory profile for EOX which should encourage the use of this regimen around the world in the perioperative setting of resectable, gastric, and GO adenocarcinomas. Given the ease of administration of EOX without the need for central venous access, ECF may only have a place for use in patients who present with gastric outlet obstruction and cannot swallow oral capecitabine.
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[Table 1], [Table 2], [Table 3]