Keywords adenocarcinoma of the stomach - fluorouracil - leucovorin - oxaliplatin - docetaxel
chemotherapy - locally advanced - metastatic
Introduction
Gastric cancer is the fifth most common cancer among males and the seventh among females
in India. It is also the second most common cause of death globally.[1 ]
[2 ]
In India, the age-adjusted rate (AAR) of gastric cancer is 3.0 to 13.2, whereas the
global AAR for gastric cancer ranges between 4.1 and 95.5.[3 ]
[4 ]
[5 ]
[6 ]
Indian patients are usually locally advanced or metastatic at presentation. As weight
loss and loss of appetite are a significant concern, treatment with aggressive regimens
at full dose to extract maximum benefit from chemotherapy becomes an uphill task.
Optimization of a standard regimen to improve survival with minimal toxicities is
the need of the hour in gastric cancers.
There is no universal standard chemotherapy regimen in first-line treatment for locally
advanced or metastatic adenocarcinoma, and the prognosis is still abysmal with a median
survival of 6 to 10 months despite treatment with combination chemotherapy, but for
modified docetaxel, cisplatin, and fluorouracil (DCF) regimen by Manish Shah et al
documented a median progression-free survival (PFS) and overall survival (OS) of 9.7
and 18.8 months, respectively, in a randomized Phase II study with lesser toxicities
in comparison with the standard DCF regimen; however, randomized Phase III trials
have shown that combination chemotherapy improved survival and quality of life compared
with best supportive care.[7 ]
In the early days, two-drug combination of fluorouracil (FU) and cisplatin-containing
combinations was considered standard therapy for patients with advanced gastric cancer
in terms of response rate with no survival benefit.[8 ] Later, there was evidence that showed that the addition of DCF was superior to cisplatin
and FU alone (CF) in terms of quality of life, response rate, time to progression,
and OS.[9 ]
[10 ]
[11 ] Despite these benefits, standard DCF is criticized and not preferred due to its
toxicity profile but a modified DCF triplet regimen was considered the standard of
care in the first-line treatment of locally advanced and metastatic adenocarcinoma
of the stomach.[12 ]
Several oxaliplatin-based regimens have been evaluated for gastric cancer,[13 ]
[14 ]
[15 ]
[16 ] with the most intensively investigated regimen being a biweekly (once every 2 weeks)
combination of infusional 5-FU (24 hour), leucovorin, and oxaliplatin (FLO).[17 ]
[18 ]
[19 ] This regimen (FLO) has fewer toxicities and thromboembolic events when compared
with that of the cisplatin-based regimen.[13 ] The results of FLO regimen raised the interest of using this regimen with docetaxel
instead of the classical CF regimen.[20 ]
In 2008, Al-Batran, in a Phase II trial with FU, leucovorin, oxaliplatin, and docetaxel
(FLOT) chemotherapy in metastatic gastric cancer, showed a significant response rate
of 57.7%, with a median PFS of 5.2 months and an OS of 11.1 months in the Western
population. The quadruple FLOT regimen has been the new standard of care for locally
advanced and resectable gastric adenocarcinoma after the FLOT-4 study. Indian gastric
cancers are extremely cachexic with poor oral intake at the time of diagnosis and
have varied tolerance with increased toxicities while treated with standard DCF regimen.
Using lower doses of docetaxel and replacing cisplatin with oxaliplatin in FLOT compared
with standard DCF was hypothesized to improve survival outcomes with a better toxicity
profile; hence, this study was taken up to assess the safety and efficacy of FLOT
chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel in our patient
population.
Materials and Methods
Study Design
This is a single-center, prospective study of patients with locally advanced and metastatic
gastric adenocarcinoma who required chemotherapy, treated at Amrita Institute of Medical
Sciences, Kochi, between March 2016 and November 2017.
Inclusion Criteria
Those with histologically confirmed or biopsy-proven adenocarcinoma of the stomach
who receive chemotherapy with FLOT regimen
Those with age >18 years
Those with Eastern Cooperative Oncology Group[21 ] PS 2 or less
Those with no history of synchronous or double malignancy
Those in locally advanced gastric cancer (defined as clinical stages T3N1 or T4N1
as determined by computed tomography [CT] scans and endoscopic ultrasonography)
Patients willing to abide and sign an informed consent.
Exclusion Criteria
Patients with proven preexisting peripheral neuropathy.
Those with brain metastasis.
Those with cancers arising from the gastroesophageal junction and squamous cell histology.
Those with cardiac dysfunction, human immunodeficiency virus-positive patients, or
those with other immunodeficiency syndromes
Those with a history of hypersensitivity to FLOT chemotherapeutic drugs.
The FLOT four-drug regimen constitutes 5-fluorouracil, leucovorin, oxaliplatin, and
docetaxel. The dose of each drug was as follows: 5-FU at 1200 mg/m2 /day as a 24-hour infusion on days 1 and 2, docetaxel at 50 mg/m2 , and oxaliplatin at 85 mg/m2 each as a 2-hour intravenous (IV) infusion on day 1. Injection leucovorin at 400 mg/m2 was administered as IV infusion on days 1 and 2. The drugs were cycled every 2 weeks
or once in 14 days, and up to a total of eight cycles were given for patients with
metastatic disease. In locally advanced gastric adenocarcinoma, four cycles of neoadjuvant
(preoperative) chemotherapy followed by surgery and four more cycles of adjuvant (postoperative)
chemotherapy were planned. Reassessment was performed at the completion of four cycles
of FLOT, and toxicities were noted at the end of every cycle.
Standard antiemetic prophylaxis was done as per institution protocols. Prophylactic
dexamethasone 8 mg was administered (days: 0–2) to prevent fluid retention and allergic
reactions. Three doses of prophylactic growth factors (granulocyte colony-stimulating
factor or Grafeel 300 µg subcutaneous once daily for 3 days) from day 3 of chemotherapy
after each cycle were permitted. In patients with Grade IV toxicities or febrile neutropenia,
50% dose reduction was permitted with increase in use or prophylactic growth factor.
Before treatment, a complete general physical examination along with past medical
history, complete blood count, blood chemistry, and pretreatment CT scans of chest,
abdomen, and pelvis (CAP) was done 3 weeks prior to start of the treatment.
Toxicity was evaluated before the start of each cycle as per the National Cancer Institute
- Common Toxicity Criteria (NCI-CTC) version 3.0.
For every four cycles, the objective response was evaluated as per the Response evaluation
criteria in solid tumors (RECIST) criteria v1.1 based on a CT-scan of CAP (magnetic
resonance imaging, when indicated) and they were compared with a baseline CT scan.
In the locally advanced setting, patients received four cycles of neoadjuvant chemotherapy
followed by four more cycles after surgery and in the metastatic setting, a maximum
of eight cycles of biweekly chemotherapy were planned. The primary objective was to
evaluate the safety and efficacy of the regimen, whereas the secondary objective was
OS and PFS.
Statistical Analysis
The data were analyzed using IBM SPSS software (Version 20.0 for Microsoft). With
FLOT regimen, the efficacy was calculated using the percentage of cases with response
to treatment.
Kaplan–Meier survival curves were plotted to measure the OS rates and PFS rates.
OS is defined as the time from randomization to death from any cause.
PFS is defined as the time from randomization until the first evidence of tumor progression
or until death from any cause, whichever comes first.
Ethics
The procedures followed were in accordance with the ethical standards of the responsible
committee on human experimentation (institutional) and with the Helsinki Declaration
of 1964, as revised in 2013. Ethical committee approval was obtained from Amrita Institute
of Medical Sciences Ethics Committee, IEC-AIMS-2017-MEDONCO-472 on 26–12–2017. Informed
patient consent was obtained prior to enrolment of participants.
Results
A total of 28 patients were treated with the FLOT chemotherapy regimen. Their mean
age was 55.7 ± 9.8 years (range, 28–70 years), and there was a male preponderance
(89.3%). [Table 1 ] depicts the demographics of patients with gastric adenocarcinoma included in the
study.
Table 1
Patients' general characteristics with locally advanced and metastatic adenocarcinoma
of stomach
General characteristics
Number of patients, n (%)
Stage
III
3 (10.7)
IV
25 (89.3)
Sex distribution
Male
25 (89.3)
Female
3 (10.7)
Lauren classification
Diffuse
14 (50.0)
Intestinal
14 (50.0)
Among the 28 patients, nearly 90% of the patients had stage IV disease, that is, 25
patients had metastatic disease (89.3%), while locally advanced disease (10.7%) was
noted in three patients. Six patients (21.4%) had undergone prior tumor removal or
gastrectomy who later relapsed. Various prior treatments are summarized in [Table 2 ].
Table 2
Various previous treatments received
Prior treatment
n (%)
Surgery
6 (21.4)
Perioperative chemotherapy
6 (21.4)
Radiation
1 (3.5)
No prior treatments
22 (78.5)
Among the 25 patients (89.3%) with metastatic disease, 32% had metastasis to liver
parenchyma, followed by a colon (21%), peritoneal, and ascites (17.8%). One in five
patients who received FLOT had metastasis to two or more locations at the time of
diagnosis ([Table 3) ].
Table 3
Different sites of metastasis at the time of presentation
Site of metastasis
Number of patients, n (%)*
Liver
9 (32.1)
Colon
6 (21.2)
Peritoneum with ascites
4 (14.2)
Omentum
4 (14.2)
Peritoneum
2 (7.1)
Lung
1 (3.5)
Ovary
1 (3.5)
Bone
1 (3.5)
Adrenal
1 (3.5)
Skin
1 (3.5)
Note: * signifies the various sites of metastasis and the commonest site of involvement
at the time of diagnosis.
Safety
A total of 139 cycles of FLOT were administered, with a mean of 4.5 cycles per patient
(range, 1–8), and majority (75%) of the recruited patients received at least four
cycles (n = 21).
The most common hematological toxicity was all-grade neutropenia (75%), followed by
febrile neutropenia in ten patients (35.7%). The most common nonhematological toxicities
were fatigue and mucositis. Various hematological and nonhematological toxicities
are depicted in [Tables 4 ] and [5 ], respectively. As a result of increased adverse events, dose modification was noted
in 57.12% (16) of the patients after a mean of 3.1 cycles.
Table 4
Hematological toxicities associated with fluorouracil, leucovorin, oxaliplatin, and
docetaxel chemotherapy regimen
Toxicity
Grade
Number of patients
Total, n (%)
Neutropenia
2
6
20 (71.4)
3
9
4
5
Anemia
2
3
7 (25.0)
3
3
4
1
Thrombocytopenia
2
2
7 (25.0)
3
2
4
3
Table 5
List of nonhematological toxicities with fluorouracil, leucovorin, oxaliplatin, and
docetaxel chemotherapy regimen
Toxicity
Grade
Number of patients
Total, n (%)
Mucositis
2
0
10 (35.7)
3
9
4
1
Peripheral neuropathy
2
4
9 (32.1)
3
4
4
1
Diarrhea
2
2
8 (28.5)
3
6
4
6
Fatigue
2
0
10 (35.7)
3
6
4
4
Chemotherapy with FLOT had to be discontinued in seven patients (25%) after one cycle
due to various reasons. The cause of discontinuation was cardiac arrest in two patients
(one succumbed to neutropenic sepsis with septic shock, while the other had a probable
5-FU-related coronary vasospasm), one patient developed a cerebrovascular accident
(embolism in the right cerebral hemisphere), three had Grade IV neutropenia with thrombocytopenia,
and one had severe fatigue and Grade IV vomiting and refused further chemotherapy.
Efficacy
Among the 28 patients who received FLOT chemotherapy, only 21 had completed at least
four cycles of biweekly chemotherapy, whereas seven patients discontinued after receiving
one cycle.
Two deaths were noted prior to the initial CT scan evaluation and were considered
as disease progression. Out of the 28 patients, 11 had an objective response with
an intent-to-treat (ITT) objective response rate of 52.3%, with the best-obtained
response being a partial response (PR) with two patients having stable disease. [Table 6 ] shows the responses obtained to FLOT chemotherapy.
Table 6
Responses obtained to fluorouracil, leucovorin, oxaliplatin, and docetaxel chemotherapy
Responses obtained
Number of patients, n (%)
CR
0
PR
11 (39.2)
ORR = CR + PR
11 (39.2) on ITT analysis, ORR = (52.3)
Progression
10 (35.7)
Stable disease
2 (7.1)
Response not assessed
5 (17.8)
Abbreviations: CR, complete response; ITT, intent-to-treat; ORR, overall response
rate; PR, partial response.
The median time to progression was 5 months (95% confidence interval [CI] [1.78–8.21])
[[Fig. 1 ]], with a median OS of 13 months (95% CI [8.14–17.85]) ([Fig. 2) ]. PFS at 1 year for stage III and stage IV on FLOT was 50 and 30%, respectively,
(95% CI [0.226–4.435]), p = 0.005 (log rank test).
Fig. 1 The disease-free survival (DFS) for the study group was 5 months (95% confidence
interval: 1.78–8.21).
Fig. 2 The overall survival (OS) for fluorouracil, leucovorin, oxaliplatin, and docetaxel
chemotherapy was 13 months (95% confidence interval: 8.14–17.85).
Discussion
The biology of gastric cancer is extremely unique and aggressive by behavior, with
most of them being either metastatic or locally advanced and inoperable at the time
of diagnosis. Despite all efforts in oncology, improving survival and quality of life
has been challenging in gastric adenocarcinoma. Platinum, taxane, and fluoroquinolone
compounds in various two or three drug combinations have been the mainstay of treatment
in gastric adenocarcinoma since the early 90s in both locally advanced and metastatic
scenarios. Treating gastric adenocarcinoma with the right combination at the optimal
therapeutic dose with tolerable side effects might most likely improve responses that
translate into a survival benefit.
In our study, we intended to assess the safety and tolerability of the FLOT regimen.
On ITT analysis, the overall response rate was 52.3%, with PR being the best-obtained
response. The median time to progression was 5 months and the median OS was 13 months
with significantly increased adverse events and more than half of the patients in
the study needed dose modifications.
The response rates were very similar to that of the reported literature, with most
of the regimens being active in gastric cancer such as ECF, XP, FOLFOX, or EOX, at
a rate of ∼45% ± 10%.[9 ]
In the landmark study, REAL-2, the median OS to ECF, XP, FOLFOX, or EOX was between
9 and 13.3 months, with a 13-month OS with FLOT regimen in our study. The reason for
no significant improvement in median OS in our patients with gastric cancer is probably
multifactorial, as the majority of our patients are emaciated, with low socioeconomic
status and had a significant weight loss either due to advanced disease (cancer cachexia
per se) or low food intake with an average weight of patients in our study being 53 kg
with a mean body surface area of 1.525.
There was a significant increase in hematological and nonhematological adverse events
with Grades III to IV neutropenia in more than half of patients despite receiving
three doses of prophylactic growth factors with every cycle. Higher grades of febrile
neutropenia were seen in one-third of the patients (35.7%) with FLOT regimen. Increased
all-grade gastrointestinal toxicity in the form of severe diarrhea and vomiting was
documented in 21.4 and 10.7% of the patients, respectively. Similarly, increased hematological
and gastrointestinal adverse events were reported with three-drug DCF regimen in the
V325 study and Al-Batrans' 2008 FLOT study with 48% Grades III to IV neutropenia and
14.8% Grades III to IV diarrhea.
More than half (57.1%) of the patients needed dose modifications due to chemotherapy-related
adverse effects, with over a quarter of the patients stopping further chemotherapy
after one cycle due to various reasons, mostly due to toxicity-related discontinuation.
The neurotoxicity related to oxaliplatin and docetaxel is well known and is the primary
reason for stopping the chemotherapy. As both drugs cause peripheral neuropathy, we
were cautious about combining them, but surprisingly, neurotoxicity was not very high
with this regimen—the 17.8% of Grade III to IV peripheral neuropathy in our study
was similar to the 17% reported in the GATE study.[22 ]
Within the limitations of small sample size, FLOT chemotherapy regimen has had some
activity in linitis plastica, which is relatively chemoresistant,[23 ] and among 13 patients with diffuse gastric cancer, we observed four PRs corresponding
to a response rate of 30.7%. The best response documented in diffuse gastric carcinoma
with signet ring cell morphology was a PR.
Four patients had extensive omental deposits with ascites at the time of presentation;
after initiating FLOT chemotherapy, ascites disappeared after three cycles in three
patients (75%), which suggests that it is an active regimen in extensive peritoneal
disease as well.
Our patients with gastric adenocarcinoma seem to have very poor tolerance to the FLOT
chemotherapy regimen with significant toxicities; hence, alternative or modified regimens
need to be explored to improve outcomes. The need of hospitalization for 2 days and
peripheral venous access such as a peripherally inserted central catheter line to
administer chemotherapy is also a major challenge as many a time the cost of treatment
has to be borne by the patient himself/herself from his/her own expenditure with no
health insurance. Hence, quadruple FLOT regimen should be considered only in a patient
with good performance status and no significantly associated comorbidities.
Conclusion
FLOT chemotherapy regimens induced excellent responses in locally advanced and metastatic
adenocarcinoma of the stomach but with significantly increased adverse events, needing
dose modifications in nearly two-thirds of the patients and hence, it should be considered
only in a young patient with good performance status and no associated comorbidities.
