Efficacy and Safety of mFOLFOX-6 in Advanced Gastric Cancer: A Prospective Observational Study

Abstract

Background

The widespread use of oxaliplatin plus infusional 5-fluorouracil (5-FU) and folinic acid (FOLFOX) in advanced gastric cancers is mainly based on clinical trials conducted at Western/European countries. The prospective data on efficacy and safety of FOLFOX in advanced gastric cancer is lacking from the developing countries. In this prospective observational study, we evaluated the efficacy and toxicity of mFOLFOX-6 in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinomas, as first-line palliative chemotherapy.

Methods

Patients with previously untreated metastatic adenocarcinoma of stomach/GEJ, received mFOLFOX-6 (2 hours infusion of oxaliplatin [85 mg/m²] and folinic acid [400 mg/m²], followed by fluorouracil 400 mg/m² intravenous push, then a 46-hour continuous infusion of 5-FU [2,400 mg/m²]). Cycles were repeated every 2 weeks. The patients were prospectively followed up for response rates and toxicity.

Results

Sixty-six patients were included in the study with a median age of 57 years. Sixty-two patients were evaluable for response. The overall response rate was 53%, with a disease control rate (overall response and stable disease) of 81.8%. The median progression-free survival was 6 months (95% confidence interval [CI] 5.2–6.7 months) and the median overall survival was 11.5 months (95% CI 9.0–13.9 months). Ascites at presentation and more than one site of metastasis are associated with significantly lower survival on the log-rank test. Gastrointestinal and hematological toxicities were predominant, with rates of grade 3 to 4 nausea/vomiting (13.6%), anemia (15.1%), and neutropenia (13.6%). Among other toxicities, neurosensory toxicities were common. Four (6%) patients had grade 3 peripheral neuropathy.

Conclusion

mFOLFOX-6 is an active and well-tolerated chemotherapy regimen in advanced adenocarcinoma of stomach/GEJ. This regimen has similar response rates and treatment outcomes with lesser grade 3 or 4 toxicities than that of triplet regimens compared to historical studies.

Keywords

advanced gastric cancer - mFOLFOX-6 - palliative chemotherapy

Amrith B. Patel

Introduction

Gastric cancer is one of the common cancers accounting for cancer-related deaths worldwide. It is the 5th most common cancer by incidence and the 4th most common cause of cancer-related deaths worldwide according to GLOBOCAN 2020.[1] The incidence is lower in Indian subcontinent when compared to that of western countries. About two-thirds of the patients with gastric cancer present in advanced stage, and are candidates for palliative treatment alone.[2] These proportions are even higher in the developing countries leading to lower 5-year survival rates.[3] Palliative chemotherapy improves survival and quality of life in patients with metastatic and locally advanced gastric cancers when compared to best supportive care (BSC) alone.[4] Fluoropyrimidines, platinum compounds, taxanes, epirubicin, and irinotecan are the commonly used active drugs in carcinoma stomach. These agents may be employed alone or in combination in first-line therapy. The studies have shown that combination chemotherapy (doublet or triplet) improves survival when compared to single-agent therapy, but at the cost of additional toxicities.[5] The armamentarium for carcinoma stomach is further expanded by the addition of targeted therapies, and more recently by the addition of immunotherapy.[6] [7] [8] [9]

There is no single accepted standard chemotherapy regimen for advanced gastric cancers in the first line. The triplet regimens improve response rates, with a significant increase in grade 3/4 adverse effects. Most advanced gastric cancer patients will have difficulty in tolerating such intensive chemotherapy in a palliative setting. So treatment approaches to prolong the life and improve quality of life must consider a careful balance of potential benefits with likely toxicities. Most of the guidelines recommended fluoropyrimidine (5-fluorouracil [5-FU] or capecitabine) and a platinum (cisplatin or oxaliplatin) based doublet as the preferred first-line option. So, a doublet chemotherapy is an acceptable treatment choice with comparable response rates and acceptable rates of toxicities. Infusional 5-FU, folinic acid, and oxaliplatin (FOLFOX) doublet is a commonly used chemotherapy regimen in advanced gastric cancers. The scope of this regimen has widened with the recent approval of nivolumab in combination with FOLFOX for advanced gastric cancers in first line.[8] The prospective data on efficacy and safety of FOLFOX in advanced gastric cancer is lacking from the developing countries. So in this prospective observational study, we evaluated the efficacy and toxicity of modified FOLFOX-6 (mFOLFOX-6) in patients with metastatic or locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinomas, as first-line palliative chemotherapy.

Patients and Methods

Patient Eligibility

Eligible adults (≥ 18 years) with histologically proven locally advanced or metastatic adenocarcinoma of stomach/GEJ, who are receiving first-line palliative chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, with adequate hematologic, renal, and hepatic functions. Patients were excluded from the study if they are ECOG PS 3 and 4, had coexistent/synchronous malignancies, or had received previous chemotherapy or radiotherapy. Participants had given written informed consent before they entered the study, which was approved by the Ethics Committees of the institute.

Chemotherapy

Patients were administered a mFOLFOX-6 regimen composed of a 2-hour infusion of oxaliplatin (85 mg/m²) and folinic acid (400 mg/m²), followed by fluorouracil 400 mg/m² intravenous push, then a 46-hour continuous infusion of 5-FU (2,400 mg/m²). Cycles were repeated every 2 weeks and treatment was continued until disease progression or unacceptable toxicity. Antiemetic prophylaxis was given according to institute protocols.

Response Evaluation

Responses and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) after the completion of four to six cycles. Based on evaluation if it was decided to continue chemotherapy, then the next reevaluation was done after completion of four to six cycles of additional chemotherapy, followed by every 3 monthly reevaluation until disease progression or death.

Toxicity Assessment

Toxicity was assessed at every visit using the National Cancer Institute Common Toxicity Criteria version 5.0. Peripheral neuropathy was graded according to the following oxaliplatin-specific scale[10]: grade 1: paresthesias/hypoesthesias of short duration with complete recovery before the next cycle; grade 2: paresthesias/hypoesthesias persisting between two cycles without functional impairment; and grade 3: permanent paresthesias/hypoesthesias resulting in functional impairment.

Statistical Analysis

Based on previous studies,[11] [12] [13] the response rate to FOLFOX chemotherapy was 30 to 40%. Taking this value as reference, the minimum required sample size with a 15% margin of error and 5% level of significance is 41 patients. Categorical variables were presented in number and percentage (%), and continuous variables were presented as mean ± standard deviation and median. Kaplan–Meier survival analysis was used to assess progression-free survival (PFS)/overall survival (OS). The log-rank test was used to compare the survival distributions. Statistical significance was defined as p < 0.05. The data was entered in MS Excel spreadsheet and analyzed using Statistical Package for Social Sciences (SPSS) version 21.0.

Results

We screened 105 histologically proven patients of carcinoma stomach/GEJ, who were found to be inoperable (locally advanced) or metastatic at presentation registered at our center. Among them, 39 patients were excluded from the study as the patients did not meet inclusion criteria, mostly due to poor performance status or patients managed with other chemotherapy regimens. Of the 66 patients included in the study, 3 patients were lost to follow-up without a radiologic response evaluation and in one patient the chemotherapy was stopped after one cycle, before any radiological evaluation due to grade 3 cardiotoxicity. At the end of the study, 62 patients were available for final analysis of efficacy. Patient characteristics are listed in [Table 1].

Table 1 Patient characteristics

Patient characteristics (N = 66)		Number of patients	Percentage (%)
Median age in years		57 (range 20–79)
Sex	Male	46	60.0
	Female	20	40.0
ECOG PS at presentation	ECOG PS 0	2	3.0
	ECOG PS 1	52	78.7
	ECOG PS 2	12	18.1
Primary site	GEJ	22	33.3
	Cardia/Fundus	3	4.5
	Body	16	24.2
	Antrum/Pylorus	4	6.0
	Linitis plastica	3	4.5
No of metastatic sites	1	30	45.4
	2	20	30.3
	> 2	16	24.2
Site of metastatic disease	Peritoneal	31	46.9
	Ascites	13	19.6
	Liver	17	25.7
	Lung	10	15.1
	Bone	8	12.1
Gastric outlet obstruction	Yes	8	12.1
	No	58	87.9

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; GEJ, gastroesophageal junction.

Efficacy

Sixty-two patients were evaluable for response at least once. Thirty-five (53%) patients had a partial response and none of the patients had a complete response, accounting for an overall response rate (ORR) of 53%. Nineteen (28.8%) had stable disease and 8 (12.2%) patients had progressive disease on first evaluation. The disease control rate (overall response and stable disease) was 81.8%. Sixty-two patients were included in the survival analysis on an intent-to-treat basis. Kaplan–Meier analysis is shown in [Figs. 1] and [2]. The median PFS was 6 months (95% confidence interval [CI] 5.2–6.7 months), and the median OS was 11.5 months (95% CI 9.0–13.9 months). Ascites at presentation and more than one site of metastasis are associated with significantly lower survival on the log-rank test ([Figs. 3] and [4], respectively).

Fig. 1 Kaplan–Meier analysis of progression-free survival.

Fig. 2 Kaplan–Meier analysis of overall survival.

Fig. 3 Ascites at presentation as prognostic factor.

Fig. 4 Number of metastatic sites at presentation as prognostic factor.

Safety

A total of 659 cycles of treatment were administered with a median of 10 cycles (range 1–20). The major reason for discontinuation of chemotherapy was progression of disease. In one patient, chemotherapy had to be discontinued before response evaluation due to grade 3 cardiotoxicity. Eight (12.1%) patients required dose reductions in at least one cycle. Toxicities observed during the treatment are listed in [Table 2]. Gastrointestinal and hematological toxicities were predominant, with rates of grade 3/4 nausea/vomiting (13.6%), anemia (15.1%), and neutropenia (13.6%). However, febrile neutropenia was seen in only two patients. Among other toxicities, neurosensory toxicities were the most common. Four (6%) patients had grade 3 peripheral neuropathy.

Table 2 Toxicities associated with the regimen

Toxicity	All grades		Grade 3 or 4
	No	%	No	%
Hematologic toxicity Neutropenia Thrombocytopenia Anemia
	29	43.9	9	13.6
	24	36.3	5	7.5
	36	54.5	10	15.1
Gastrointestinal toxicity Nausea/vomiting Diarrhea Constipation Stomatitis
	24	36.3	9	13.6
	21	31.8	6	9.0
	14	21.2	3	4.5
	11	16.6	2	3.0
Others Neurosensory toxicity Cardiac Cutaneous
	29	43.9	4	6.0
	2	3.0	1	1.5
	10	15.1	0	0

Discussion

The prognosis of metastatic gastric cancer remains poor despite advances in palliative treatment. Studies comparing combination chemotherapy with BSC only in advanced gastric cancer have consistently shown a survival benefit varying from 3 to 9 months.[14] In a retrospective review of 692 patients on palliative chemotherapy, the median OS of patients who received combination chemotherapy was significantly longer than that of the patients who received single agents (11 vs. 8 months, p < 0.0001). The ORRs with various chemotherapy regimens vary from 30 to 70%. In our study, the ORR was 53% (all partial responses) with a disease control rate of 81.8%. The median PFS was 6 months and the median OS was 11.5 months. These results were consistent with the results published in previous studies. In the phase II study by Louvet et al,[15] 49 patients with advanced gastric cancer were treated with FOLFOX and showed an ORR of 44.9% and a median survival of 8.6 months. In another prospective study of mFOLFOX-6, the ORR was 43.8% and the median time to progression and OS were 6.0 months (95% CI, 4.8–7.2 months) and 12.6 months (95% CI, 8.7–16.5 months), respectively.[16] In a phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with Advanced Gastric Cancer (AGC) by Al-Batran et al, 43% of the patients had overall response, and stable disease was observed in 32% of patients. The median OS was 9.6 months. A phase III randomized study by Al-Batran et al,[17] compared fluorouracil, leucovorin plus either cisplatin (FLP) or oxaliplatin (FLO). The median PFS, which was the primary endpoint, was 5.8 months (95% CI, 4.5–6.6 months) and the median OS was 10.7 months (95% CI, 8.5–13.9 months) with FLO. ORR with FLO in the above study was 34.8% and the disease control rate was 75.9%.

The efficacy of FOLFOX in different studies and their comparison to the present study are presented in [Table 3].

Table 3 The efficacy of FOLFOX in different studies with comparison to the present study

Study, year	N	Population	Regimen	ORR (%)	PFS (mo	OS (mo)
Louvet et al,[15] 2002	54	All ages	mFOLFOX (100/400/3000)	44.9	6.2	8.6
De Vita et al,[11] 2005	61		FOLFOX 4	38	7.1	11.2
Keam et al,[16] 2008	73	All ages	mFOLFOX6	43.8	6.0	12.6
Al-Batran et al,[13] 2004	37	All ages	FOLFOX (85/500/2600)	43	5.6	9.6
Mohammad et al,[18] 2011	34	All ages	FOLFOX4	53	9.4	12.1
Catalano et al,[12] 2013	43	Elderly, > 70 years	mFOLFOX	34.9	6.8	10.5
Present study	66	All	mFOLFOX-6	53.0	6.0	11.5

Abbreviations: FOLFOX, infusional 5-fluorouracil, folinic acid, and oxaliplatin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

We noticed that the number of metastatic sites at presentation has bearing on PFS/OS. Those patients with single sites of metastasis had significantly better PFS and OS when compared to those with more than one sites of metastasis (median PFS of 8.6 vs. 5.0 months, respectively, p = 0.05 and median OS of 13.6 vs. 9.7 months, respectively, p = 0.02). The current literature also indicates that malignant ascites at presentation is associated with poor prognosis in gastric cancer. In a systemic review and meta-analysis, 14 articles including 15 studies, 9 studies assessed the difference in prognosis between patients with and without malignant ascites. A pooled hazard ratio of 1.63 (95% CI: 1.47–1.82, p < 0.00001) indicated that gastric cancer patients with malignant ascites had a relatively poor prognosis compared to patients without ascites.[19] Similar findings are also observed in this study.

The mFOLFOX-6 regimen is generally well tolerated and the incidence of grade 3 or 4 toxicities was relatively low even in elderly patients. FOLFOX appear to be well tolerated even in elderly population with similar response rates and comparable toxicity profile. The mFOLFOX regimen resulted in an ORR of 34.9% with a median PFS and OS of 6.8 and 10.5 months, respectively, in a study among elderly patients aged > 70 years.[12] Most of the toxicities are hematological or gastrointestinal, most of them being grade 1 or 2. Neuropathy, a cumulative toxicity of oxaliplatin is a dose-limiting side effect. High rates of oxaliplatin-related neuropathy has been reported with FOLFOX6 in patients with metastatic gastric cancer and FOLFOX-4 in patients with advanced colorectal cancer (21 and 18% grade 3 neurotoxicity, after median cumulative doses of up to 900 mg/m²).[12] [15] However, in the phase 2 study of Al-Batran et al[13] the absence of grade 3 neuropathy is probably related to the low median cumulative dose of oxaliplatin (595 mg/m²) administered. In our study, four (6%) patients had grade 3 neuropathy requiring dose modifications. A careful watch on neuropathy in patients receiving oxaliplatin and dose modification if required can prevent the debilitating neurological side effects. Fluracil-related cardiac side effects are rare but may be life-threatening. The incidence varies from 0 to 19% in various studies with a wide spectrum of manifestations.[20] [21] Only one of our patients had severe chest pain and cardiac dysfunction requiring discontinuation of treatment.

mFOLFOX-6 is an active and well-tolerated chemotherapy regimen in advanced adenocarcinoma of stomach/GEJ. This regimen has similar response rates and treatment outcomes with lesser grade 3 or 4 toxicities than that of triplet regimen compared to historical studies. To the best of our knowledge, this is the first prospective study conducted in India for assessing mFOLFOX-6 as a palliative chemotherapy in advanced adenocarcinoma of stomach/GEJ. This study assures the application of western guidelines to current clinical practice in the Indian subcontinent. There is an unmet need to improve outcomes in advanced gastric cancers. Further studies are required for the use of this chemo backbone along with targeted/immunotherapies to improve outcomes of patients with advanced gastric cancer.

Conflict of Interest

None declared.

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Publication History

Received: 14 June 2023

Accepted: 26 June 2024

Article published online:
22 July 2024