Keywords gastric cancer - TEX regimen - docetaxel - oxaliplatin - capecitabine - prognostic
score
Introduction
Globally, gastric cancer accounts for 5.7% of new cases (5th most common) and 8.7%
of deaths due to cancer per year (3rd most common).[1 ] Nonmetastatic gastric and gastroesophageal junction adenocarcinoma are managed by
combined therapeutic modality (surgery, chemotherapy, and radiotherapy).[2 ] The 5-year overall survival (OS) of localized gastric cancer is 31% that has remained
stable over the last three to four decades.[3 ] Metastatic disease has an extremely poor prognosis with a 5-year OS of less than
5%.[2 ] According to Globocan 2020, gastric cancer is the sixth most common cancer in India.
India has a yearly estimate of 68,000 new cases of gastric cancer, which leads to
around 50,000 deaths.[4 ]
[5 ] Kashmir has a high incidence of gastric cancer (4th most common), accounting for
7.6% of all cancers and it exceeds the national average in India.[6 ]
[7 ] The metastatic disease is managed primarily by palliative intent chemotherapy with
surgery and radiotherapy reserved for selected indications. Systemic chemotherapy
results in better response rates, slightly prolonged survival, and improved quality
of life.[8 ]
Immunotherapy, either alone or in combination with chemotherapy, has now replaced
chemotherapy as the first-line treatment for metastatic gastric and gastroesophageal
adenocarcinoma (MGGEAC) in Western countries.[9 ]
[10 ]
[11 ] However, due to its high cost, chemotherapy remains the standard of care for patients
in low-middle income countries like India. Platinum and 5-fluorouracil (5-FU)/analogue
combination is considered the gold standard first-line regimen in this setting. The
DCF regimen (docetaxel, cisplatin, 5-FU) slightly improves response rate and survival,
but with higher toxicity, it provides an additional option for physically fit patients.[12 ]
[13 ] To reduce the toxicity, while maintaining the efficacy, different regimens were
tried. One such regimen referred to as the fluorouracil, leucovorin, oxaliplatin,
and docetaxel (FLOT) regimen has reported improved ORR with an acceptable toxicity
profile.[14 ]
[15 ]
[16 ] The modification of this regimen with the substitution of 5-FU with capecitabine
(Taxotere, Eloxatin, and Xeloda [TEX] regimen) has been tested by many investigators.[8 ]
[14 ]
[17 ]
[18 ]
In Kashmir, the diagnosis and treatment of MGGEAC are often challenging due to limited
healthcare resources; however, efforts are being made to improve the management of
these cancers in the region, including the development of specialized cancer centers
and increased access to screening and diagnostic services.[6 ] Overall, MGGEAC represents a significant burden of disease in Kashmir, and improving
awareness, prevention, and treatment strategies for these cancers in the region is
a critical public health priority.
The aim of our prospective observational study is to assess the effectiveness, safety,
and tolerability of the TEX regimen in treating MGGEAC in the Kashmir region. The
study seeks to assess the ORR, PFS, and OS of patients with MGGEAC-treated with this
regimen. This information can guide clinical practice and contribute to evidence-based
treatment guidelines for patients with MGGEAC.
Materials and Methods
Patient Selection
This prospective observational study was conducted in MGGEAC patients registered at
Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu & Kashmir from
November 2017 to December 2018. Patients who had been newly diagnosed with MGGEAC
or were developing metastatic disease after receiving definitive treatment with radical
surgery and chemoradiation, and who fulfill the following inclusion criteria, were
included in the study. Inclusion criteria were (1) age more than 18 years and less
than 70 years, (2) Eastern Cooperative Oncology Group (ECOG) performance status less
than 2, (3) no prior palliative chemotherapy, and (4) measurable disease and sufficient
renal, hepatic, and bone marrow function. However, patients with uncontrolled medical
illness, psychiatric illness, and pregnant or lactating women were excluded from the
study.
Study Design and Treatment Protocol
Eighty-five patients were enrolled in the study. History with clinical examination
was performed before enrolment. Baseline complete blood count, blood chemistries,
electrocardiogram, and serum tumor markers (Carcinoembryonic antigen (CEA), CA19–9)
were analyzed. All the enrolled patients underwent Oesophagogastroduodenoscopy (OGD)
scopy and histopathological confirmation of disease. A contrast-enhanced computed
tomography (CECT) scan of the thorax, abdomen, and pelvis was performed 2 weeks before
starting the treatment. After enrolment, patients received the TEX regimen as follows:
docetaxel 50 mg/m2 (1 hour infusion), followed by oxaliplatin 85 mg/m2 (2 hours infusion) on day 1, and capecitabine 1250mg/m2 /day twice daily for 14 days by oral route. The cycle was repeated every 14 days.
Administration of prophylactic treatments, such as antiemetics and corticosteroids,
was based on standard recommendations and physician assessment. Granulocyte colony-stimulating
factor was used for secondary prophylaxis. Treatment continued as long as the disease
progressed, there was unacceptable toxicity, or the patient refused treatment. Dose
modifications were performed according to published guidelines.
Assessment of Response and Tolerability
The patients were evaluated for their response to chemotherapy after each treatment
cycle. They underwent a CECT scan after completing four cycles of chemotherapy or
earlier if the physician deemed it necessary. The scans were evaluated by at least
two observers and confirmed by an independent radiologist. The assessment of radiological
response was determined using the RECIST 1.1 criteria.[19 ] Results were stratified as complete response (CR), partial response (PR), stable
disease, or progressive disease. The period of PFS was calculated from the commencement
of chemotherapy until the first indication of disease progression or death. In the
absence of any such events, the last follow-up date was considered as the end-point
for PFS measurement. The OS period was calculated from the beginning of chemotherapy
until the patient's death due to any cause, or until the last follow-up date if the
patient was still alive. Toxicity assessments were conducted in each cycle using the
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
version 4.0. OS and PFS were further evaluated with univariate and multivariate analyses.
A prognostic score proposed by Chau et al, which includes ECOG performance status
more than or equal to 2, SAP levels more than 100, presence of peritoneal metastases,
and presence of liver metastases were calculated and patients were divided into three
groups (no risk factors, one or two risk factors, ≥3 risk factors).[20 ]
Statistical Analysis
The utilization of descriptive statistics, such as median, frequency, and percentage,
was employed to depict categorical variables encompassing age, gender distribution,
treatment, and response to treatment. All patients were assessed for the ORR, which
was expressed as a percentage and considered as the primary end-point. The secondary
end-points were PFS, OS, and safety. PFS and OS were evaluated using Kaplan–Meier
survival methods, whereas univariate and multivariate comparisons analysis was done
by log-rank test. IBM SPSS version 20.0 (SPSS Inc. Chicago, Illinois, United States)
was used for statistical analyses.
Ethics
The Ethical Standards by the Institutions and National Research Committee, Helsinki
Declaration of 1964, and subsequent amendments or equivalent standards have been complied
with for all procedures undertaken in this study. The study was approved by the Institutional
Ethics Committee of SKIMS, Soura, Jammu & Kashmir (Protocol number 65/2018 dated 07.07.2018),
and conducted in compliance with protocol after written informed consent to participate
in the study was taken from all patients before enrolment.
Results
Patient Demographics
The study enrolled a total of 85 patients between November 2017 and December 2018.
The data from 85 patients diagnosed with gastric (n = 61) and gastroesophageal junction (n = 24) adenocarcinomas who underwent treatment with the TEX regimen was analyzed.
Her2 neu tested positive in 8 out of 38 biopsy samples ([Table 1 ]).
Table 1
Patient dispositions and demographics
Baseline characteristics
No. of patients (percentage, if required)
Total no. of patients evaluated
85
Median age
60 (26–70 years)
≤ 60 years
55 (64.7%)
> 60 years
30 (35.3%)
Sex
Male
70 (82.4%)
Female
15 (17.6%)
ECOG PS
≤1
75 (88.2%)
≥2
10 (11.8%)
Location of primary
GE junction/proximal
30 (35.3%)
Body
24 (28.2%)
Distal
27 (31.8%)
No localization
4 (4.7%)
Prior surgery and chemoradiation
No
79 (92.9%)
Yes
6 (7.1%)
Site of metastases
Nonregional node
38 (44.7%)
Liver
36 (42.4%)
Peritoneum
28 (32.9%)
Lung
7 (8.2%)
No of sites of metastases
1
44 (51.8%)
≥2
41 (48.2%)
Histology
Adeno
69 (81.2%)
Signet
16 (18.8%)
Her2Neu (by FISH/IHC)
Positive
8 (9.4%)
Negative
30 (47.1%)
Not performed
47 (55.3)
Chau prognostic group
No risk factor
9 (10.6%)
1/2 risk factor
69 (81.2%)
3/4 risk factor
7 (8.2%)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; FISH,
fluorescence in situ hybridization; IHC, immunohistochemistry.
Efficacy
Median number of chemotherapy cycles delivered was eight cycles (1–15). After completion
of four cycles of the TEX regimen, we evaluated a total of 85 patients and found that
one of them achieved a CR, which corresponds to a percentage of 1.2%. Additionally,
53 patients showed a PR, representing a percentage of 62.4%. Thus, ORR was 63.5% (54/85).
In 21 patients (24.7%), the disease remained stable. In addition, only 10 patients
(11.8%) showed progressive disease ([Table 2 ]). Maintenance capecitabine was received by 32 patients (37%) after getting a favorable
response on the TEX regimen. Upon progression, 62% of patients (33/53) received second-line
chemotherapy. The most common second-line chemotherapy used was single-agent irinotecan
(70%).
Table 2
Tumor response to Taxotere, Eloxatin, and Xeloda (TEX) regimen after completion of
four cycles
Number of eligible patients
85
No of patients performed response assessment scan
78
Radiologic response
Frequency (%)
Complete response
1 (1.2)
Partial response
53 (62.4)
Stable disease
21 (24.6)
Progressive disease
10 (11.8)
Overall response rate
54 (63.5)
Clinical benefit rate
75 (88.2)
Having observed clinical responses of the tumor against the TEX regimen after four
cycles, next, we evaluated PFS and OS as secondary end-points of our study. The median
follow-up period was 10.5 (3–27) months. The duration of median PFS was noted to be
9.1 months (standard error: 1.15, 95% confidence interval [CI]: 6.84–11.23 months).
Similarly, the median OS noted was 13 months (standard error: 1.53; 95% CI: 10.01–15.99
months; [Fig. 1 ]).
Fig. 1 Kaplan–Meier curve for progression-free survival (PFS) (A ) and overall survival (OS) (B ). CI, confidence interval; SE, standard error.
Univariate Analysis of OS and PFS with Prognostic Factor Score
In the univariate analysis, a single metastatic site had shown better progression-free
survival (PFS), which retained significance in multivariate analysis (8.5 vs. 2.7
months; p -value 0.035). ECOG performance status, presence of nonregional lymph nodal disease,
and capecitabine maintenance had significant effects on PFS in univariate analysis,
whereas none of these factors showed significance in multivariate analysis. For OS,
capecitabine maintenance had shown significance in univariate analysis, but not shown
significance in multivariate analysis ([Tables 3 ] and [4 ]).
Table 3
Univariate and multivariate analyses of PFS
Characteristics
PFS (months)
p -Value (univariate analysis)
p -Value (univariate analysis)
Age
0.338
0.986
≤ 60
6.271
> 60
4.987
Gender
0.681
0.731
Male
5.999
Female
5.259
ECOG
PS
0.011
0.175
0.1
10.026
≥2
1.232
Location of primary
0.927
0.578
GE junction/
Proximal
6.134
Body
6.020
Distal
6.367
No localization
3.996
Histopathological reports
0.848
0.140
Adeno
5.820
Signet ring cell
5.438
TB
0.588
0.418
N
6.181
> ULN
5.078
ALP
0.126
0.233
< 100 U/L
7.015
> 100 U/L
4.243
Presence of nonregional nodal metastases
0.043
0.345
Yes
7.678
No
3.580
Presence of peritoneal metastases
0.149
0.324
Yes
3.672
No
7.587
Presence of liver metastasis
0.632
0.234
Yes
5.109
No
6.150
No. of sites of metastases
0.045
0.035
(HR: 0.017, 95% CI: 0.000–0.759)
1
8.525
≥2
2.734
Chau prognostic score
0.244
0.117
No risk factors
2.065
1,2 risk factors
4.525
3,4 risk factors
10.298
Capecitabine
maintenance
0.004
0.857
Yes
7.776
No
3.483
Abbreviations: ALP, Alkaline phosphatase; CI, confidence interval; ECOG PS, Eastern
Cooperative Oncology Group performance status; GE, gastroesophageal junction; HR,
hazard ratio; PFS, progression-free survival; TB, total bilirubin; ULN, upper limit
of normal.
Table 4
Univariate and multivariate analyses of OS
Characteristics
OS (months)
p -Value (univariate analysis)
p -Value (multivariate
analysis)
Age
0.479
0.341
≤ 60
7.760
> 60
6.689
Gender
0.953
0.344
Male
7.284
Female
7.164
ECOG PS
0.053
0.111
0,1
10.996
≥2
3.453
Location of primary
0.992
0.760
GE junction/proximal
6.834
Body
7.220
Distal
7.633
No localization
7.209
Histopathological reports
0.486
0.147
Adeno
8.014
Signet ring cell
6.434
TB
0.670
0.109
N
6.715
> ULN
7.733
ALP
0.726
0.826
< 100 U/L
7.579
> 100 U/L
6.869
Presence of nonregional nodal metastases
0.088
0.290
Yes
9.183
No
5.265
Presence of peritoneal metastases
0.471
0.124
Yes
6.126
No
8.322
Presence of liver metastasis
0.987
0.813
Yes
7.244
No
7.204
No. of metastases
0.080
0.312
1
10.209
≥2
4.239
Chau prognostic score
0.851
0.280
No risk factors
6.215
1,2 risk factors
6.569
3,4 risk factors
8.888
Capecitabine maintenance
0.001
0.874
Yes
10.064
No
4.384
Abbreviations: ALP, Alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group
performance status; GE, gastroesophageal junction; OS, overall survival; TB, total
bilirubin; ULN, upper limit of normal.
Assessment of Safety Profile
Next, we checked for TEX regimen safety and tolerability. Neutropenia was the most
observed grade ¾ toxicity (36.7%). Anemia and fatigue were the second most common
toxicity, affecting 20% of the participants. Febrile neutropenia and sensory neuropathy
were reported in 16.7 and 8.3%, respectively. There were no deaths related to the
treatment. Twenty-four of the patients required dose reductions ([Table 5 ]).
Table 5
Adverse events
Toxicity
Any grade
Number (%)
Grade 3 and 4
Number (%)
Hematological
Neutropenia
31 (51.7%)
22 (36.7%)
Anemia
35 (58.33)
12 (20%)
Thrombocytopenia
17 (28.3%)
8(13.3%)
Febrile neutropenia
(Grade 3 and 4 only)
–
10 (16.7%)
Nonhematological
Fatigue
35 (58.3%)
12 (20%)
Sensory neuropathy
17 (28.3%)
5 (8.3%)
Diarrhoea
17 (28.3%)
4 (6.7%)
Mucositis
12 (20%)
4 (6.7%)
Hand foot syndrome
24 (40%)
4 (6.7%)
Anorexia
24 (40%)
3 (5%)
Nausea and vomiting
18(30%)
3 (5%)
Discussion
Systemic treatment in MGGEAC aimed to improve survival, pain control, quality of life,
and nutritional intake. The Cochrane meta-analysis[13 ] showed that systemic chemotherapy improves median survival and response rate compared
with placebo. The combination chemotherapy regimen is superior to single-agent chemotherapy
in terms of survival and response rate with slightly increased toxicity.[21 ] There is no ideal first-line chemotherapy regimen, which could be either a doublet
of a platinum agent with 5-FU/analogue, or a triplet of docetaxel combined with platinum
and 5-FU/analogue. The selection is based on patient performance status, general health,
comorbid illnesses, and patient preference.[22 ]
Docetaxel-based triplet regimens for advanced gastric cancer have become more common
following the results of the V-325 trial of Van Cutsem et al 2006, which concluded
that the use of DCF resulted in improved clinical outcomes and survival compared with
only CF regimen,[14 ] but with higher frequency of adverse events (82% severe neutropenia, 29% febrile
neutropenia and 49% severe gastrointestinal adverse events).
To reduce the toxicity of the DCF regimen, while maintaining its efficacy, researchers
introduced a modified DCF regimen.[23 ]
[24 ]
[25 ] Another approach was to substitute cisplatin with oxaliplatin and 5-FU with capecitabine,
which is called TEX regimen.[14 ]
[18 ] A comparison of the REAL-2 meta-analysis and ML17032 trial has revealed that capecitabine-based
combinations offer improved OS when compared with 5-FU.[26 ] Al-Batran et al data showed decreased toxicity with oxaliplatin compared with cisplatin-based
chemotherapy.[27 ]
A trial using the FLOT regimen[15 ] for MGGEAC reported an ORR of 57.7%, median PFS, and OS of 5.2 and 11.1 months,
respectively. Grade 3/ 4 toxic effects were neutropenia (48.1%), leukopenia (27.8%),
diarrhea (14.8%), fatigue (11.1%), and febrile neutropenia in 3.8%.
According to Srinivasalu et al,[28 ] ORR, 1-year PFS, and higher-grade toxicities were 52, 60, and 33%, respectively,
in the FLOT group. Febrile neutropenia and thrombocytopenia were the most common toxicities.
Another trial[29 ] concluded that the docetaxel, oxaliplatin, and 5-fluorouracil regimen (docetaxel + FOLFOX
7) provided a high response rate (72%) at the cost of increased toxicity (72% grade
¾).
Stein et al[18 ] conducted a study which revealed that the TEX regimen resulted in an overall response
rate (ORR) of 43%. The study also found that the median PFS was 6.9 months, and the
OS was 13 months. The most common higher grade toxicities were diarrhea (30%), nausea/vomiting,
and infections.
A study conducted by Tata Memorial Hospital in Mumbai, India, analyzed the TEX regimen
in MGGEAC. The ORR was 55.2%, and a clinical benefit rate was 80.8%. The median event-free
survival was 6.34 months and the median OS was 15.3 months.[8 ] The most common higher grade adverse events were hand-foot syndrome (22.5%), neutropenia
(19.2%), diarrhea (17.7%), anemia (9.6%), and neuropathy (7.2%).
Van Cutsem et al[14 ] randomly assigned patients with MGGEAC into three arms—TE, TEF, and TEX. ORR, median
PFS, and median OS in the TEX arm were 25.6%, 5.55 months, and 11.30 months respectively.
Febrile neutropenia was reported in 9% (TEX) of patients. Other toxicities were similar
across the arms.
Our study is prospective, and to the best of our knowledge, it is the largest study
to feature the TEX regimen in the region of Kashmir. We reported a higher ORR (63.5%)
and better median PFS (9.1 months) in comparison with published literature. Median
OS (13 months) was comparable.[8 ]
[14 ]
[15 ]
[18 ]
[28 ]
[29 ] Single site of metastases had shown better PFS in our study.
Neutropenia and anemia of grade ¾ were noticed in 36.7 and 20% of patients, respectively.
Additionally, only 16.7% of patients had febrile neutropenia. These toxicities are
comparable with other studies of FLOT and TEX regimens and much lesser compared with
the DCF regimen. Additionally, the incidence of nonhematological toxicities was lower
compared with the modified DCF regimen[23 ]
[24 ] and was comparable with other studies of FLOT and TEX regimen.[8 ]
[14 ]
[15 ]
[18 ]
[28 ]
[29 ] These findings suggest that the TEX regimen may be associated with a lower risk
of certain toxicities, making it a potentially viable treatment option for patients
with MGGEAC.
Merits of our study were prospective nature, real-world setting, adequate patient
numbers, daycare delivery of chemotherapy, avoidance of peripherally inserted central
catheter line and its complications, lesser toxicity, and better response rates. This
is the first study from Jammu and Kashmir, supporting the use of the TEX regimen.
The limitations of the study were primarily observational nature, shorter follow-up,
and no comparison arm. We did not use trastuzumab in this study because it is not
combined with three-drug regimens in other trials.
Conclusion
In MGGEAC, the TEX regimen gives superior response rates and numerically higher PFS.
A higher number of sites of metastases is a poor prognostic factor in MGGEAC, which
has been seen in our study. The trial needs a longer follow-up for updated results,
and we recommend a randomized controlled study comparing CapeOx with TEX to test this
regimen further.
