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Phase II Study of Oxaliplatin, Fluorouracil, and Folinic Acid in Locally Advanced or Metastatic Gastric Cancer Patients

From the Hôpital Saint-Antoine, Hôpital Tenon, and Hôpital St Joseph, Paris; Hôpital de Villeneuve St Georges, Villeneuve St Georges; Centre Paul Papin, Angers; Centre René Gauducheau, Saint Herblain; Centre Institut Bergonié, Bordeaux; Centre Antoine Lacassagne, Nice; Centre François Baclesse, Caen; Cvitkovic et Associés Consultants, Kremlin-Bicêtre; and Hôpital Ambroise Paré, Boulogne, France.

Address reprint requests to Christophe Louvet, MD, Service d’Oncologie-Médecine Interne, Hôpital Saint-Antoine, 184, Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France; email: christophe.louvet{at}sat.ap-hop-paris.fr

	ABSTRACT

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PURPOSE: To evaluate the efficacy and safety of an oxaliplatin, fluorouracil (5-FU), and folinic acid (FA) combination in patients with metastatic or advanced gastric cancer (M/AGC).

PATIENTS AND METHODS: Of the 54 eligible patients with measurable or assessable M/AGC, 53 received oxaliplatin 100 mg/m² and FA 400 mg/m² (2-hour intravenous infusion) followed by 5-FU bolus 400 mg/m² (10-minute infusion) and then 5-FU 3,000 mg/m² (46-hour continuous infusion) every 14 days.

RESULTS: Patients (69% male, 31% female) had a median age of 61 years (range, 31 to 75 years), 89% had a performance status of 0 or 1, 70% had newly diagnosed disease, and 87% had metastatic disease. All had histologically confirmed adenocarcinoma. With a median of three involved organs, disease sites included the lymph nodes (67%), stomach (65%), and liver (61%). A median of 10 cycles per patient and 468 complete cycles were administered. Best responses in the 49 assessable patients were two complete responses and 20 partial responses, giving an overall best response rate of 44.9%. Eight patients underwent complementary treatment with curative intent (six with surgery and two with chemoradiotherapy). Median follow-up, time to progression, and overall survival were 18.6 months, 6.2 months, and 8.6 months, respectively. Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and anemia occurred in 38%, 19%, 4%, and 11% of patients, respectively, and febrile neutropenia occurred in six patients (one episode each). Grade 3 peripheral neuropathy occurred in 21% of patients (oxaliplatin-specific scale). Seven patients withdrew because of treatment-related toxicity.

CONCLUSION: This oxaliplatin/5-FU/FA regimen shows good efficacy and an acceptable safety profile in M/AGC patients, and may prove to be a suitable alternative regimen in this indication.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
UNTIL 1988, GASTRIC adenocarcinoma was the leading cause of cancer death worldwide. It is diagnosed approximately twice as often in men as in women, and is more frequent in the elderly, the mean age of diagnosis being 70 to 73 years. With most cases being diagnosed at an advanced stage, the prognosis for this disease is extremely poor, with 5-year survival ranging from 5% to 15%.¹ The only potentially curative treatment for localized gastric cancer is surgery. Chemotherapy, which may or may not be associated with radiotherapy, is used to treat advanced/metastatic disease. The efficacy of chemotherapy with palliative intent is now widely accepted.²

Fluorouracil (5-FU) is one of the most effective and widely used drugs in the treatment of advanced gastric cancer (AGC), producing a response rate of approximately 20%, with manageable toxicity.³ Overall survival of between 5 and 7 months has been reported for 5-FU monotherapy in phase III randomized studies.^4,5 5-FU modulation by folinic acid (FA) has generally resulted in enhanced antitumor efficacy (22% to 48% overall response rate) and has led to some complete responses (5% to 9%).^6-9 All current reference combination regimens in AGC contain 5-FU.

Cisplatin, an active agent in monotherapy, has also been introduced into a 5-FU/anthracycline regimen (doxorubicin- and epirubicin-containing protocols) and, more recently, combined with 5-FU alone (FP combination), using various modalities (5-day continuous infusion; high-dose, 24-hour protracted continuous intravenous infusion; and modulation with FA).

Many combinations have been widely used in AGC, such as 5-FU, doxorubicin, and mitomycin (FAM); 5-FU, doxorubicin, and high-dose methotrexate (FAMTX); etoposide, doxorubicin, and cisplatin (EAP); etoposide, leucovorin, and 5-FU (ELF); epirubicin, cisplatin, and 5-FU continuous infusion (ECF); cisplatin, epirubicin, leucovorin, and 5-FU (PELF); and several regimens of cisplatin and 5-FU. In randomized studies, FAMTX, cisplatin/5-FU, and PELF have been demonstrated to be more effective than FAM,^4,10,11 FAMTX and EAP,¹² FAMTX, cisplatin/5-FU, and ELF¹³ and showed no significant differences in survival. ECF was reported as more active than FAMTX.¹⁴ However, despite response rates of up to 51% in these trials, the median survival in patients with advanced disease consistently remained below 10 months. Moreover, toxicities such as leukopenia or alopecia are often present in anthracycline- and/or etoposide-based regimens. Therefore, despite the lack of studies comparing ECF versus any FP combination, cisplatin and 5-FU remains widely used as first-line treatment of advanced gastric carcinoma. It was thus logical to test oxaliplatin in this indication.

Oxaliplatin (cis-[oxalato(trans-l-1,2-diaminocyclohexane) platinum (II)]) is a third-generation diaminocyclohexane platinum compound proven to be active in various tumor types in animals and in the clinical setting. It has been approved in the treatment of advanced colorectal cancer, giving a single-agent response rate of 10% in patients resistant to 5-FU^15,16 and, in combination with 5-FU with or without FA as first-line treatment, a rate of 36% to 58%.^17-20 It has also shown activity in several other malignancies, such as ovarian, lung, head and neck, and pancreatic cancer.^21-25 Oxaliplatin has a higher preclinical antitumoral potency than cisplatin in models such as the HT29 colon cell line,²⁶ and has demonstrated synergy with 5-FU in vitro, in vivo, and in the clinical setting in advanced colorectal cancer.^27,28 It presents a better toxicity profile than cisplatin, its main and dose-limiting toxicity being acute, cumulative short-term sensory peripheral neurotoxicity, resulting in acral paresthesia/dysesthesia, exacerbated by cold.²⁹ The FOLFOX6 regimen^20,30 was chosen for the present study, and was evaluated according to objective response rate, time to progression, overall survival, and its safety profile in a multicenter trial setting.

	PATIENTS AND METHODS

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Patient Population
To be eligible for this study, patients had to have pathologically confirmed, nonresectable locally advanced or metastatic malignant gastric cancer; at least one measurable lesion in a nonirradiated area; not received prior chemotherapy; a World Health Organization performance status 2; been aged between 18 and 75 years; a life expectancy 12 weeks; and adequate hepatic, renal, and bone marrow function. Patients were excluded from the study if they were experiencing symptomatic peripheral neuropathy of National Cancer Institute (NCI) common toxicity criteria (CTC) grade 2; were pregnant or breast-feeding or were of child-bearing potential without using adequate contraception; had any other current or prior malignancy (with the exception of excised cervical carcinoma in-situ or squamous cell skin carcinoma treated by surgery only); showed clinical evidence of major organ failure; had CNS metastases; had bone metastases as the sole disease site; had active noncontrolled infection or disease; had a neurologic or mental disease not consistent with an adequate comprehension of the patient information sheet; or were receiving concurrent treatment with any other drugs that could potentially interfere with the study evaluation (such as long-term administration of corticosteroids). The protocol was approved by the local ethics committee, and signed informed consent was obtained from all patients.

Study Design
In this multicenter, nonrandomized, open-label, phase II trial, patients received oxaliplatin 100 mg/m² and FA 400 mg/m² in 5% glucose, administered simultaneously as a 2-hour intravenous infusion. This was followed by bolus 5-FU 400 mg/m² administered as a 10-minute infusion, immediately followed by 5-FU 3,000 mg/m² as a continuous infusion over 46 hours. Treatment was repeated every 14 days. Treatment was continued for at least six cycles except in the event of disease progression, unacceptable toxicity, patient refusal, or physician decision. Patients presenting a complete response received treatment for no more than 1 year. Antiemetic treatment (5-hydroxytryptamine type with or without corticosteroids) was always administered before the oxaliplatin infusion.

In the event of toxicity (NCI-CTC), the following dose reductions and treatment delays were planned. In cases of insufficient hematologic function (neutrophil count < 1,500/mm³, platelet count < 100,000/mm³) on day 14 of any cycle, treatment was delayed for up to 14 days. If recovery did not occur at this point, the treatment was discontinued. Any 5-FU dose reductions were only applied to the continuous infusion. For grade 2 or 3 thrombocytopenia and grade 3 or 4 neutropenia, there was a 20% 5-FU dose reduction. For grade 3 or 4 gastrointestinal toxicities or grade 3 hand-foot syndrome, 5-FU was reduced by 20%. For grade 2 cardiotoxicity, 5-FU treatment was discontinued. In cases of paresthesia/dysesthesia accompanied by pain lasting longer than 7 days, oxaliplatin was reduced by 20%. In cases of paresthesia/dysesthesia with functional impairment persisting between cycles, oxaliplatin was omitted in further cycles until recovery.

Study Evaluations
In the week preceding treatment, patients underwent a complete medical history, a physical examination, and an ECG. A chest radiograph, a computed tomographic scan of the abdominal area and of all measurable/assessable sites, a magnetic resonance imaging scan if indicated, evaluation of nonmeasurable lesions, and an ultrasound endoscopy (for locally advanced disease) were carried out in the 4 weeks preceding treatment. Baseline biologic analyses (blood cell count, serum creatinine, bilirubin, AST, ALT, lactate dehydrogenase, alkaline phosphatase) were measured at baseline and before each cycle, with the exception of alkaline phosphatase and bilirubin, which were measured every two cycles. The tumor markers carcinoembryonic antigen and CA 19-9 were measured at baseline and every two cycles.

All adverse events, except peripheral sensitive neuropathy, were graded using the NCI-CTC (version 1) at each cycle. Peripheral sensitive neuropathy was graded according to the following oxaliplatin-specific scale, modified from Caussanel et al³¹: 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 paresthesia/dysesthesia resulting in functional impairment. Tumor evaluation was intended to be carried out every six cycles during therapy according to standard World Health Organization criteria³² with the appropriate clinical and radiologic examinations, and responses were to be confirmed within 4 weeks. Patients going off study for reasons other than disease progression were to be evaluated every 3 months in follow-up visits. Responses were to be reviewed by an external review panel. Patients were considered assessable for response if early disease progression occurred or if they had received at least six cycles of treatment, with at least one follow-up tumor assessment. The duration of partial response (PR) or no change was from the beginning of treatment until the documentation of progression, and the duration of complete response was from the time of complete response (CR) documentation until progression. Time to progression (TTP) was measured from initial treatment to progression, date of last contact, or start of subsequent antitumor therapy. If the patient underwent complete resectional surgery, TTP was measured from initial treatment until documentation of progression after surgery. Overall survival (OS) was measured from initial treatment until death.

The expected number of patients for this study was calculated according to a Simon optimal two-stage design. An interim analysis was carried out when the first 15 assessable patients had been recruited. If more than five responses were observed, 31 additional patients were to be recruited; otherwise, the study was to be terminated. If more than 18 responses were observed in the 46 patients (response rate > 39.1%), the regimen was considered sufficiently active to be submitted for further evaluation. TTP and OS were analyzed according to the Kaplan-Meier method, and were updated to May 1, 2001.

	RESULTS

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Patient Characteristics
Fifty-seven patients were initially enrolled onto this study in 10 French centers between September 24, 1997, and June 19, 2000. Three patients were considered ineligible and were not evaluated in the current analysis, two of whom had a second active neoplasia (lymphoma and urothelial bladder carcinoma), and the other patient had nonmeasurable disease. Thus, the current analysis was carried out with the remaining 54 enrolled patients with gastric adenocarcinoma. One of the eligible patients refused treatment after being enrolled onto the study, and thus the safety analysis was performed on 53 patients.

Patient characteristics are listed in Table 1. The median patient age was 61 years (range, 31 to 75 years); 37 patients were male (69%) and 17 were female (31%), with most patients being in good general condition (89% with a performance status of 0 or 1). All patients had histologically confirmed adenocarcinoma, the majority of which were moderately or well differentiated (48% or 26%, respectively). The median number of organs involved was three (range, one to five), with 27 patients (50%) having at least three organs involved. The most common disease sites were the lymph nodes (36 patients [67%]: locoregional [65%] and distant [22%]), stomach (35 patients [65%]), and liver (33 patients [62%]). In 70% of patients, disease was newly diagnosed, and 87% of patients had metastatic disease, including three patients (5.6%) who had only distant node metastases. Twenty-seven patients (50%) had undergone previous surgery.

Best responses are shown in Table 2. All objective responses (confirmed and unconfirmed) were reviewed by an external expert committee. Of the 49 assessable patients, two (4%) had CRs and 20 (41%) had PRs, giving an overall best response rate of 44.9% (95% confidence interval, 30.7% to 59.1%). Four of the PRs were not formally confirmed: one patient underwent combined chemoradiotherapy after six cycles of study treatment, one patient left the study four cycles after the initial PR assessment, and for two patients, evaluation was not performed until six and eight cycles after the initial PR assessment, by which time their disease had progressed. It is important to note that for each of these patients, the time to progression was within the range of the other patients with confirmed responses. Fourteen patients (29%) reported stable disease (SD). When considering all 54 eligible patients, the response rate was 22 of 54 (40.7%; 95% confidence interval, 27.3% to 54.1%). With one exception, all responding patients were metastatic, 16 having hepatic metastases.

Time-related efficacy parameters for the 53 eligible treated patients were updated to May 1, 2001. Median follow-up was 18.6 months (range, 10.4 to 43.1 months). Median time to progression was 6.2 months (range, 0.2 to 38.3+ months), and the median OS was 8.6 months (range, 0.2 to 38.8+ months) (Fig 1). Of the 15 patients who had been followed for at least 12 months, eight (53%) were still alive after 1 year.

View larger version (16K): [in this window] [in a new window]   Fig 1. Overall survival.

Median relative dose-intensities were 89% for oxaliplatin (range, 53% to 102%), 90% (range, 27% to 102%) for FA, and 81% for 5-FU (range, 49% to 102%). Median cumulative doses were 901 mg/m² for oxaliplatin, 28,503 mg/m² for 5-FU, and 3,422 mg/m² for folinic acid. Ninety-four of the 415 (23%) cycle intervals were delayed in 37 patients (71%), with 12% of cycle intervals being delayed for more than 7 days. Most cycle delays (58 of 94 [62%]) were because of treatment-related toxicity, and 20% (19 of 94) were for personal convenience. Of the 52 patients who received more than one cycle, 27 (52%) had at least one dose reduction in a total of 38 cycles (9%). Nine patients (17%) had a dose reduction in both oxaliplatin and 5-FU. As expected, the majority of oxaliplatin dose reductions were because of neurotoxicity (79% of delayed cycles), and most 5-FU reductions were a result of hematotoxicity (70% of delayed cycles).

Seven patients (13%) discontinued treatment because of treatment-related adverse events, five for neurotoxicity, one for cardiotoxicity (5-FU–induced recurrent pectoral angina), and one for digestive toxicity. One death was considered likely to be treatment related (because of pleural effusion and septic shock, without neutropenia).

Toxicities experienced during treatment are listed in Table 3. The most common toxicity was hematologic, with neutropenia, leukopenia, thrombocytopenia, and anemia being reported in 68%, 62%, 72%, and 91% of patients, respectively, and being severe (grade 3 or 4) in 38%, 19%, 4%, and 11% of patients, respectively. It is important to note that after implementation of dose reductions, these toxicities were diminished, a fact reflected in the number of cycles of toxicity experienced, with severe neutropenia, leukopenia, thrombocytopenia, and anemia being present in 8%, 3%, 1%, and 3% of cycles, respectively. Six patients (11%) each experienced one cycle of febrile neutropenia. These patients all had dose reductions that prevented recurrence of this toxicity.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This multicenter study was motivated by the need for an effective therapy in this poor-prognosis patient population. The externally reviewed best OS (44.9%) and CR (4%) rates in the assessable population reported here using this FOLFOX6 regimen of oxaliplatin/5-FU/FA are in the same range as those reported in phase II studies using FAMTX, ELF, EAP, and ECF and more recently in studies using taxane- or irinotecan-based regimens, which have shown overall response rates of between 30% and 70% and CR rates of 5% to 10%.^33-45 It is of note that in a recent pilot North American phase II study in which patients with upper gastric and lower esophageal adenocarcinoma with oxaliplatin/5-FU/FA were treated using a regimen similar to that used in the present study, the response rate was 46%, with a good safety profile.⁴⁰

The median TTP of the 53 patients analyzed in this study was 6.2 months, and the median OS was 8.6 months. These time-related parameters are similar to those reported in multicentric randomized comparative studies, such as the study using ECF and FAMTX (OS of 8.7 and 6.1 months, respectively),¹⁴ and that comparing FAMTX, ELF, and FUP (OS rates of 6.7, 7.2, and 7.2 months, respectively).¹³ It is of particular note that overall survival in this study is equivalent to that reported for the most current reference combination, ECF.^14,39,41 Furthermore, the potential for a curative multimodality approach in responders is noteworthy, because eight patients had investigator-initiated complementary treatment (surgery/chemoradiotherapy), six of whom were still alive at the study cutoff date.

Treatment compliance for this regimen was good, with the median relative dose-intensity for oxaliplatin, FA, and 5-FU being 89%, 81%, and 90%, respectively. This is further supported by the fact that only 23% of cycles were delayed and dose reductions were implemented in only 9% of cycles. In addition, treatment was maintained over a lengthy time period, with a median of 10 administered cycles (range, one to 17 cycles).

As expected with oxaliplatin-containing regimens, peripheral neuropathy is clearly the limiting toxicity, being reported in 87% of the population, and was severe (grade 3) in 21% of patients. Nonetheless, this peripheral neuropathy only occurred in patients benefiting from the treatment (ie, patients who responded or had SD), with a median cumulative dose of 901 mg/m².

Hematologic toxicity was also reported; however, it was rarely more severe than grade 3. Severe toxicity was restricted by dose reductions, allowing patients to continue with treatment. The absence in this study of deaths resulting from hematologic toxicity reflects the limited occurrence of febrile neutropenia (six patients, each experiencing a single episode), a toxicity that is a common cause of morbidity and toxic deaths in anthracycline-containing regimens. Grade 3 or 4 thrombocytopenia, stomatitis, and diarrhea are in the same range as that reported in other regimens. Severe nausea-vomiting occurred less frequently (6% of patients) as compared with other platinum-based regimens (ECF and FUP). Grade 2 alopecia was reported in only 9% of patients, which is less frequent compared with other anthracycline- or etoposide-based regimens (ECF, FAMTX, and ELF). Table 4 lists the toxicity of these regimens. It is also of note that only one patient in this study experienced central venous catheter complications and that no anticoagulant prophylaxis was administered.

	ACKNOWLEDGMENTS

 
Supported by a grant from Sanofi-Synthelabo, France, Le Plessis-Robinson, France.

We thank Yacine Salhi, MD, for statistical analysis; Sarah Mackenzie, MD, for her help in editing the article; Youssef Yataghene, MD (Sanofi-Synthélabo), for comments; and the following for their participation: M.L. Garcia, P. Artru, F. Maindrault, J. Gligorov, F. Selle, J. Bennouna, and V. Barbarot.

	NOTES

 
Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 19-23, 2000.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted February 5, 2002; accepted July 29, 2002.

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