Early outcomes of surgical treatment with perioperative chemotherapy for gastric cancer

Gastric cancer is one of the leading digestive cancers concerning incidence and mortality rate. Surgery plays the main role of a multimodal approach to treatment. This research was to evaluate the early results of surgery with perioperative chemotherapy in the treatment of gastric cancer.

EARLY OUTCOMES OF SURGICAL TREATMENT WITH PERIOPERATIVE CHEMOTHERAPY FOR GASTRIC CANCER

Bui Trung Nghia, Trinh Hong Son

Oncology Department, Viet Duc University Hospital Gastric cancer is one of the leading digestive cancers concerning incidence and mortality rate Surgery plays the main role of a multimodal approach to treatment This research was to evaluate the early results of surgery with perioperative chemotherapy in the treatment of gastric cancer Methods: descriptive, uncontrolled case series Results: n = 9 including 7 males: 2 females Neo-adjuvant chemotherapy indications included local invasion, lymph node metastasis and liver metastasis One patient had progression during treatment Toxicity was mostly of grade I or II Surgery included total (5 patients) and partial gastrectomy (4 patients) with resection of neighboring organs (6 patients) Standard lymphadenectomy was D2 up to D4 Average operating time was 287 ± 92.4 minutes [180:480] Pathology was mostly poorly differentiated adenocarcinomas or ring-cell carcinomas There was no perioperative morbidity and mortality Average postoperative stay was 9 ± 3 days [6:17] After 1 year of following up, all patients had adjuvant chemotherapy Among them, two patients had progression, one of whom died as a result Conclusion: Multimodal treatment with the combination of surgery and chemotherapy is feasible with acceptable results and could help to improve the possibility of curative treatment.

I INTRODUCTION

Keywords: gastric cancer, perioperative chemotherapy, surgery.

Gastric cancer ranks fourth in incidence

with about 1 million newly - diagnosed cases

annually and third for cancer – related deaths

worldwide with about 723,000 cases in 2012

[1] Vietnam leads Southeast Asia countries

concerning prevalence (24.4 in males and

14.6 in females) as well as mortality (14.0 per

100,000 of population) [2] The 5-year survival

rate for gastric cancer is only around

20-30% worldwide, with the exception of Japan

with 68.2%, thanks to an effective screening

program for early diagnosis and curative surgery with standard D2 lymphadenectomy [3; 4]

Gastrectomy with D2 lymphadenectomy has been considered the primary treatment for gastric cancer worldwide from Japan [5]

to European countries (ESMO) [6] and the United States of America (NCCN) [7] In the era of multi-modal treatment, neo-adjuvant and adjuvant chemotherapy is increasingly recognized as a best choice in the combination with surgery for advanced, locally invasive or metastatic gastric cancer with proven efficacy

Corresponding author: Bui Trung Nghia, Oncology

gastric cancer in the Oncology Department,

Viet Duc University Hospital

II METHODS

1 Subjects

Gastric adenocarcinoma cases were

operated after neoadjuvant chemotherapy at

the Oncology Department, Viet Duc University

Hospital from 01/6/2017 to 31/7/2018

2 Methodology

Descriptive study with uncontrolled cases

series

The patient was diagnosed as gastric

adenocarcinoma and treated by neoadjuvant

chemotherapy at the Oncology Department,

Viet Duc University Hospital or other medical

facilities but transferred to the department

for surgery The collected data included

administrative information, signs and symptoms,

characteristics of lesions in gastroscopy,

CT scanner, neoadjuvant chemotherapy

regimens including EOX (Epirubicine 50mg/

m2, Oxaliplatine 130 mg/m2, Capecitabine

1250mg/m2 bpd, 21 days per cycle) and FLOT

(Oxaliplatine 85 mg/m2, Calcium folinate

200 mg/m2, 5-FU 2600 mg/m2, Docetaxel

50 mg/m2, 14 days per cycle) and their

indications (local invasion, distant metastasis,

significant lymph node metastasis found

during preoperative examination, assessment

of treatment response based on diagnostic

imaging devices such as computerized

tomography, PET, tumor response, surgical

treatment including type of surgery: partial

or total gastrectomy, resection of invaded or

metastatic organs, lymphadenectomy level,

radical level (R0: clean resection margin in both gross and microscopic view; R1: clean

in gross but residual in microscopic view; R2: residual in gross view) and postoperative complications (surgical site infection – red, hot, swollen wound with dirty discharge, fever

or other sign of local and systemic infection; bleeding – both intra-abdominal and at the surgical sites with or without change in blood test; pancreatic leakage – amylase test of drainage discharge at 3rd day after operation was 3 times more than amylase level in the blood following criteria of International Study Group of Pancreatic Fistula; lymphatic leakage – drainage discharge more than 300 ml / day in

3 consecutive days with or without quantitative test of lipid over 110 mg/dL) as well as recorded treatment and results, recovery time of bowel movements (gaz) and postoperative hospital stay, pathology The patient was re-examined

at the time of 3 weeks after hospital discharge

to decide on the next treatment and to be monitored periodically every 1-3 months to record related events

RECIST (Response Evaluation Criteria In Solid Tumors) [9]

At the time of surgical decision, tumor response with preoperative chemotherapy was assessed using the RECIST standard 2009 that

is based on target lesions, clinical examination and imaging tests (ultrasonography, computerized tomography, endoscopy ) Target lesions are measurable lesions, up to 5 (max 2 lesions per organ) The sum of highest diameters of lesions is used as the basis for the assessment response

Table 1 Evaluation of solid tumor response according to RECIST

Evaluation RECIST guideline, version 1.1

CR

(complete response) Disappearance of all targeted lesions and reduction of short diam-eter of metastatic lymph nodes below 10 mm

PR

(partial response) Reduction ≥30% of total highest diameters of targeted lesions in comparison with original one

PD

(progressive disease)

Augmentation ≥20% or at least 5 mm of total highest diameters

in the comparison with smallest size of total highest measurable diameters

Or appearance of new lesions including ones detected by PET –

CT

SD

(stabilized disease) Without criteria of PR and PD

Assessment of toxicity and side effects of chemotherapy regimens following WHO standards

Table2 Toxicity in hematopoietic system

Toxicity Unit Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Leukopenia 103/ml ≥ 4,0 3,0 - 3,9 2,0-2,9 1,0 - 1,9 < 1,0 Neutropenia 103/ml ≥ 2,0 1,5 - 1,9 1,0-1,4 0,5 - 0,9 < 0,5

Thrombocytopenia 103/ml N 75 - N 50 - 74.9 25 - 49.9 < 25

Table3 Toxicity in liver and kidney function

Toxicity Unit Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Creatinine µmol/l N < 1,5xN 1,5 - 3,0xN 3,1 - 6,0xN > 6,0xN

Urea mmol/l < 1,5xN 1,5 - 2,5xN 2,6 - 5,0xN 5,1 - 10xN > 10xN

Bilirubin mmol/l N - < 1,5xN 1,5 - 3,0xN > 3,0xN

Transaminase UI/ml N ≤ 2,5xN 2,6 - 5,0xN 5,1 - 20xN > 20xN

Glucose mmol/l < 6,5 6,5 - 8,9 9,0 - 13,9 14 - 27,9 ≥ 30 or ketoacidosis

N: normal range

Collected data was entered and analyzed in SPSS 18.0 with statistical algorithm

3 Ethical Considerations of the patients, themselves or their legal

- Sexuality: 7 males (77.8%) / 2 females (22.2%).

- Age: 57 ± 11.3 [33:66]

Our study group had the superiority in males and mostly middle aged

2 Neo-adjuvant chemotherapy indications

Table 4 Indicatins of neo-adjuvant chemotherapy

Neoadjuvant regimens: EOX – 8 cases and

FLOT – 1 case

3 Tumor response with preoperative

chemotherapy

Of the 9 cases of the study group, there

were only three cases of partial response (PR)

and five cases of stable, non-progressive (SD)

disease There were no cases of complete

response (CR) and one case of progressive

disease (PD)

Toxicity on the hematopoietic system was

mostly at grade II with the most common

was anemia (6 out of 9 cases accounted for

66.67%) Toxicity on liver and kidney function

was common at grade 0 and I (8/9 cases

accounted for 88.89%)

4 Surgical treatment

Surgical procedures: There were five cases

of total gastrectomy (55.56%) and 4 cases of partial gastrectomy (44.44%) Six out of nine cases (66.67%) were associated with resection

of surrounding organs, most common is liver metastasectomy (including segmentectomy, left lobectomy and RF – 3/6 ~ 50%) and splenopancreatectomy (2/6 ~ 33%) All of the cases were with standard lymphadenectomy D2 (dissection of lymph nodes around the liver pedicle and celiac trunk) to D4 (dissection of lymph nodes of group 16)

Average operating time was 287 ± 92.4 minutes [180:480]

No intra-operative complication was recorded Two cases (22.22%) needed blood transfusion with 2 – 4 packed red blood cells unit

Figure 1 Radical level of surgery

In the study group, 2/9 cases (22.2%) were not considered radical operation because of unresectable liver and peritoneal metastasis

Table 5 Post-operative complication (N=9)

Post-operative complication n Ratio %

Among them, antibiotic treatment was

indicated in 3 days after operation in normal

cases but 5 days with presence of surgical

site infection even though a regular dressing

changes was required every day during

hospitalized period and at home until full

wound healing

There was one case of lymphatic leakage

with surcharged abdominal drainage of more

than 300 ml / day in 3 days but it was well

controlled by letting patient fast in 5 days with

subcutaneous octreotide of 0.1 mg/ml x 3 times

a day

presence of general peritonitis, conservative treatment was indicated and patient could discharge at 15th day after operation with drainage that was removed 2 weeks after at his visit in the consultation of the department

In our group, no re-operation was needed Average time of bowel peristaltic recovery:

3 ± 1 days [2:5]

Average post-operative stay: 9 ± 3 days [6:17]

5 Pathology

One-hundred percent of the cases were

Figure 2 Differentiation leve

6/9 cases (66.67%) were with lymph nodes metastasis

6 Follow – up results

Re-examination at the time of 1, 3, 6, 9

and 12 months after discharging from hospital

showed that all cases were treated with

adjuvant chemotherapy; 2/9 cases (22.2%)

showed progression including 1 case of

axillary lymph nodes at 6 months and 1 liver

metastasis causing jaundice at 1 month One

death was recorded 6 months after operation

and 8 cases are still being followed

IV DISCUSSION

Neo-adjuvant chemotherapy is indicated

as a "down-staging" approach to advanced

gastric cancer that aims to increase the ability

to perform radical surgery For high-risk cases

of distal metastases such as T3 / T4 tumors,

metastatic lymph nodes were observed on

imaging diagnostic devices with characteristics

such as loss of normal structure, diameter > 1

cm or linitis plastic, an unnecessary surgery

could be avoidable if distant metastatic lesions

develop during chemotherapy In three large

clinical trials with direct confrontation between

the surgical group and the neoadjuvant

chemotherapeutic group, two trials showed

superior survival benefit in the cohort The

MAGIC trial was conducted in the United Kingdom on 503 resectable gastric cancer cases, which showed that combination group (3 preoperative and 3 postoperative) had a higher rate of curative surgical intervention (79

vs 70%), higher 5-year survival rates (36 vs 23%) as well as overall survival and disease-free survival compared to surgery alone group while tolerance is acceptable with toxicity of grade 3 or 4 less than 12% [10] Similar results were reported in the FNCLCC / FFCD trial in France with 224 cases of gastric cancer of stage

II or higher with a higher rate of radical surgery (R0), lower lymph node metastasis recurrence rate (5-year survival rate of 34% vs 19%) and lower mortality (5-year survival rate of 38%

vs 24%) in the combination chemotherapy group (2 - 3 preoperative cycles and 3 - 4 postoperative cycles) vs surgical alone group [11] The EORTC (European Organization for Research and Treatment of Cancer) trial had a higher rate of radical surgery (82% vs 67%) but did not show improvements in overall survival and disease-free survival rate of combination group versus surgical group [12] In our study group, although there was not a long enough follow-up period for accurate evaluation, a

high rate of radical surgery (77.78%) and

one-year mortality was low with one in nine

because of early progression This was a case

of progressive disease with the presence of

hepatic multi-focal metastases leading to

non-radical surgery (R2)

Although no recommendations have been

made regarding the choice of chemotherapy

regimens, many clinicians have selected

Epirubicine – based regimens with three

preoperative and three postoperative cycles

in the MAGIC study However, as the disease

progresses, some clinicians tend to prolong

neoadjuvant chemotherapy up to a maximum

of 6 cycles due to a high risk of surgical

intervention In our study, 8 of 9 cases were

treated with EOX protocol including Epirubicine,

Oxaliplatine and Capecitabine Recently, with

positive results from Phase II and III trials in

response rates versus Epirubicine, FLOT

(Docetaxel, Oxaliplatine, Leuvocorin and 5 - FU)

were preferred for resectable local advanced

gastric cancer [13] In our study, 1 case was

treated with this protocol (4 preoperative and

4 postoperative cycles) with good results The

most common toxicity was febrile leukkopenia

of grade II, nausea, vomiting and headache

Surgical indication is considered after

neoadjuvant chemotherapy with 3 EOX cycles

or 4 FLOT cycles For those who respond fully

or partially, the intervention is quite clear and

easily accepted by the surgeon and the patient

However, for non-responders, especially for

lymph node as well as distant metastases,

optimal option remains unclear due to poor

prognosis [14] In our study, only 5 out of 9

cases followed the recommended protocol (3

surgical treatment was given as an opportunity

to approach the radical treatment of the patient

or what called “salvage solution” 100% of cases in the study were indicated postoperative chemotherapy with same regimens as preoperative protocol However, some authors argue that if preoperative regimens do not work, it might not be effective after surgical intervention [15]

In terms of surgery, most authors agree that radical surgery offers the best long-term survival for gastric cancer patients, especially when combined with neo-adjuvant and adjuvant therapy [10; 16] However, the biggest problem

is to diagnose patients at the focal stage In the United States of America, up to two thirds of cases were diagnosed in stage III or IV, while only 10% were in stage I according to TNM classification [17] It is highly dependent on screening programs where Japan has become

a worldwide particularity, with more than half the cases diagnosed at early stage [18]

To assess the preoperative stage for treatment indications, clinicians often rely on imaging diagnostic tools such as computer tomography, endoscopic ultrasonography to assess on-site invasiveness, such as nodal metastasis and distant metastases The ability to resect thoroughly depends on the subjective assessment, level and experience

of the surgeon but is generally consistent in the following points: distant metastasis, invasive blood vessels such as aorta, celiac trunk, hepatic arteries, mediastinal nodal metastases (out of surgical area), local invasion, especially

in the pancreas Although not absolute, but Whipple surgery for treatment of gastric cancer

medical conditions attached In our study, three

out of nine cases had surgical exploration,

lymph node biopsy and injury assessment,

of which one had emergency surgery due to

perforation and bleeding

In the study group, there were 5 cases

of total gastrectomy and 4 cases of partial

gastrectomy While indications are quite clear

with partial distal gastrectomy due to cancer at

the antrum and pylorus [19], the indication for

total gastrectomy was considered preferable

to proximal gastrectomy due to similar 5-year

survival rate (64% vs 61%) but lower recurrent

rate (24 vs 39%) and less complications such

as anastomotic stricture (7 vs 27%) or reflux

(2 vs 20%) [20] Laparoscopic surgery is

indicated only in cases of early gastric cancer,

which is not included in the study group In

the study group, only one case of patients

underwent laparoscopic surgery for lymph

node biopsy where gastric lesions were unclear

but suspected lymph node metastasis

Lymphadenectomy is also a controversial

topic in the treatment of gastric cancer as

Asia-Pacific countries tend to more extensive

dissection of lymph nodes than Western

countries Lymphadenectomy level are based

on the 16 groups of lymph nodes classification

of Japanese surgeons D1 consists of lymph

nodes surrounding the stomach (1 - 7), D2

consists of D1 and lymph nodes surrounding

hepatic pedicle, left gastric artery, splenic artery

and celiac trunk (1 - 12a) and D3 - 4 includes D2

and lymph nodes along the aorta In addition, in

the Japanese literature, a D1 + was defined as

D1 and 8a, 9 and 11p groups As clinical trials

do not show the superiority of extensive lymph

node dissection (D3, D4) [21; 22], standard

D2 lymphadenectomy is recommended for the

treatment of advanced gastric cancer but only

in big centers and with experienced surgeons

Spleno-pancreatectomy is not recommended unless there is direct invasion of the tumor [23]

In our study group, 100% of the cases were with standard lymph nodes dissection D2 to D4 with low incidence of complications: one case

of lymphatic leakage and one case of leukemia that responded well to medical treatment No surgical intervention was required In a different study, the rate of intra-abdominal hemorrhage was 0.33%, hemorrhage at the surgical site infection was 5.23% [24]

Regarding anato-pathological findings, the majority of cases in the study group were poorly differentiated adenocarcinoma or ring cell (very poorly differentiated) This is also consistent with the degree of malignancy progression and neoadjuvant treatment indication Trinh Hong Son summarized 537 cases of gastrectomy for cancer in Viet Duc University Hospital from 1993 to 1997 with mostly (95.7%) of adenocarcinomas [25] Postoperative follow-up showed one case

of recurrent hepatic metastasis, which occurred very early after surgery This was a progression after 3 cycles of EOX but only detectable during operation with the presence of unresectable multi-focal hepatic lesions Therefore, surgical resection in this case was palliative (R2) In addition, one case of peritoneal metastasis was also considered non-radical surgery (R1) despite removal of all visible peritoneal with clear margin The remaining cases were considered radical surgery with gastrectomy, lymphadenectomy of the standard D2 to D4 and removal of invaded organs into the block such as splenopancreatectomy, removal

of peritoneal capsule of pancreas, left liver lobectomy (tumor invaded to Glisson capsule but not into biliary ducts and liver parenchyma – negative resection margin) Besides, two cases with radio-frequency onto single hepatic

metastasis in segment 7 and segment 3 were

considered radical although there was no

international consensus relating to resection of

the liver due to metastases from gastric cancer

and apparently no statistically significant

association with survival time [26; 27]

V CONCLUSION

Despite of the small size of study group

and lack of long-time follow-up, surgery with

perioperative chemotherapy seems to be able

to improve the possibility of radical surgery

with acceptable morbidity rate and

non-postoperative mortality However, surgery is

still considered the best chance for advanced

stomach cancer patients Obviously,

multi-center studies with large numbers are needed

for more accurate assessment

Acknowledgments

I would like to express my gratitude and

appreciation to Professor Trinh Hong Son,

my personal tutor and also to Department of

Postgraduate Study, Hanoi Medical University

and Viet Duc University Hospital where I have

received a lot of support and assistance

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