Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  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


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 Publication9-Jan-2015

Correspondence Address:
Bhawna Sirohi
Consultant Medical Oncologist - GI and Breast Cancers, GI Disease Management Group, Tata Memorial Centre, Mumbai, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.146122

Rights and Permissions
 > Abstract 

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.

 > Abstract in Chinese 

对于可切除的局部晚期胃食管癌,奥沙利铂、卡培他滨和表柔比星,就像表阿霉素、顺铂和氟尿嘧啶化疗一样“MAGIC”

摘要

背景:表阿霉素、顺铂和氟尿嘧啶(ECF)的围手术期使用,显着提高胃和胃食管(GO)癌患者的结果,但是管理繁锁。我们分析给予与ECF方案相当的表阿霉素,奥沙利铂和卡培他滨方案(EOX),对局部晚期但可手术癌症患者中的依从性、疗效和围手术期毒性。

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。

结果:共99例(男性76%,平均年龄51岁)患者接受围手术期的EOX方案治疗。术前,93%例患者完成了EOX。新辅助化疗后,4例病情进展,1例死亡,94例做了手术。其中,9例不能切除,85例患者行根治性手术。有71%(60/85)可以完成3个疗程的辅助卡培他滨。完成6个疗程围手术期化疗的占64%。在我们的病例中,除了更多数量的腹泻,3级和4级的毒性与MAGIC资料组都是有可比性的。

结论:对于可切除胃食管腺癌,可能给予MAGIC类型的围手术期EOX化疗将有更好的依从性、毒性和疗效。

关键词:表阿霉素,奥沙利铂和卡培他滨,依从性,胃癌,治疗


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 23];10:866-70. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/866/146122


 > Introduction Top


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, [1],[2],[3],[4] 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 [5] 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. [4] 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. [6] In India, too, we adopted the MAGIC regimen [7] but found the epirubicin, cisplatin and fluorouracil (ECF) regimen (proposed by the MAGIC trial) cumbersome owing to inherent problems such as higher toxicities [7] and also difficulties in the need for central venous access. This led us to try out a number of other regimens [7] based on the literature from other trials (conducted in patients with advanced gastric cancer), including the REAL-2 trial. [3],[8] The REAL-2 trial [3] 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 [7] 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 Top


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 [7] 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 [7] 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. [9] 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.

Statistical analysis

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 Top


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

Click here to view


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.

Surgery

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

Click here to view


Adjuvant chemotherapy

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)

Click here to view



 > Compliance to all six cycles of chemotherapy Top


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 Top


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. [1],[4],[10] 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 [6],[7],[11],[12] 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. [7] 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. [11],[12] We have compared our results with the MAGIC data.

On comparing our data with the ECF regimen in the MAGIC trial, [4] 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. [7] 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. [13],[14] 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. [11],[12]
Table 3: Comparison of compliance, toxicity and efficacy profile of EOX in published literature

Click here to view


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, [15] in gastric cancer, [16] too, completion of the planned chemotherapy cycles is an independent prognostic factor. Mirza et al. [17] 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 Top


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.

 
 > References Top

1.
Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: An FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011;29:1715-21.  Back to cited text no. 1
    
2.
Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725-30.  Back to cited text no. 2
    
3.
Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36-46.  Back to cited text no. 3
[PUBMED]    
4.
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20.  Back to cited text no. 4
    
5.
Quiros RM, Bui CL. Multidisciplinary approach to esophageal and gastric cancer. Surg Clin North Am 2009;89:79-96, viii.  Back to cited text no. 5
    
6.
Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, et al. Management of gastric cancer in Asia: Resource-stratified guidelines. Lancet Oncol 2013;14:e535-47.  Back to cited text no. 6
    
7.
Shrikhande SV, Barreto SG, Talole SD, Vinchurkar K, Annaiah S, Suradkar K, et al. D2 lymphadenectomy is not only safe but necessary in the era of neoadjuvant chemotherapy. World J Surg Oncol 2013;11:31.  Back to cited text no. 7
    
8.
Chong G, Cunningham D. Can cisplatin and infused 5-fluorouracil be replaced by oxaliplatin and capecitabine in the treatment of advanced oesophagogastric cancer? The REAL 2 trial. Clin Oncol (R Coll Radiol) 2005;17:79-80.  Back to cited text no. 8
[PUBMED]    
9.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-16.  Back to cited text no. 9
    
10.
Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, et al. Gastric cancer: ESMO-ESSO-ESTRO Clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi57-63.  Back to cited text no. 10
    
11.
Kalachand R, Mongan A, Doherty M, King S, O′Farell N, Reynolds F, et al. Perioperative epirubicin, oxaliplatin, and capectabine (EOX) in locally advanced resectable gastroesophageal junction and gastric adenocarcinoma. J Clin Oncol 2013;31 [Suppl; abstract e15142].  Back to cited text no. 11
    
12.
Chen W, Shen J, Pan T, Hu W, Jiang Z, Yuan X, et al. FOLFOX versus EOX as a neoadjuvant chemotherapy regimen for patients with advanced gastric cancer. Exp Ther Med 2014;7:461-67.  Back to cited text no. 12
    
13.
Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 2011;29:4387-93.  Back to cited text no. 13
    
14.
Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): A phase 3 open-label, randomised controlled trial. Lancet 2012;379:315-21.  Back to cited text no. 14
[PUBMED]    
15.
Valle JW, Palmer D, Jackson R, Cox T, Neoptolemos JP, Ghaneh P, et al. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: Ongoing lessons from the ESPAC-3 study. J Clin Oncol 2014;32:504-12.  Back to cited text no. 15
    
16.
Qu JL, Li X, Qu XJ, Zhu ZT, Zhou LZ, Teng YE, et al. Optimal duration of fluorouracil-based adjuvant chemotherapy for patients with resectable gastric cancer. PLoS One 2013;8:e83196.  Back to cited text no. 16
    
17.
Mirza A, Pritchard S, Welch I. The postoperative component of MAGIC chemotherapy is associated with improved prognosis following surgical resection in gastric and gastrooesophageal junction adenocarcinomas. Int J Surg Oncol 2013;2013:781742.  Back to cited text no. 17
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Methods>Results>Compliance to al...>Discussion>Conclusions>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed2973    
    Printed67    
    Emailed1    
    PDF Downloaded180    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]