Abstract

BACKGROUND: At present, there is no standard regimen for the treatment of gastroesophageal cancer. Docetaxel, cisplatin and fluorouracil (DCF) has been shown to be an effective regimen; however, toxicity is an area of concern in the palliative case setting. Capecitabine and oxaliplatin have been shown to be as effective as fluorouracil and cisplatin, respectively. To reduce the toxicity of DCF while maintaining efficacy, we conducted this study to evaluate the efficacy of docetaxel, oxaliplatin and capecitabine (DOX) combination in advanced gastroesophageal cancer.
PATIENTS AND METHODS: Patients with histologically confirmed metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction received docetaxel 25 mg/m² and oxaliplatin 50 mg/m² on days 1 and 8 with capecitabine 625 mg/m² twice daily from day 1-14, in 21-day cycles. The primary endpoint was overall response rate (ORR).
RESULTS: Of 21 patients, there were 16 males and 5 females with a median age of 57 years, range 37-80 years. The primary tumor was located at the gastroesophageal junction in 7 patients and in other parts of the stomach in the remaining 14 patients. One patient had locally advanced tumor without distant metastases and 20 patients presented with metastatic disease. Grade 3/4 toxicities included diarrhea (24%), hand-foot syndrome (5%) and febrile neutropenia (5%). The ORR was 29%. The median survival was 8.4 months. At the time of analysis, 5 of the 21 patients (24%) were alive.
CONCLUSIONS: The DOX combination is tolerable, active and a promising day-care regimen for advanced gastroesophageal cancer.

Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancer deaths worldwide.¹ Patients with gastric cancer typically present with advanced disease and it continues to carry a poor prognosis. The role of palliative chemotherapy is therefore of utmost importance.

Single agents with activity in advanced gastric cancer include 5-fluorouracil (5FU), cisplatin, the anthracyclines (doxorubicin and epirubicin), mitomycin C, and etoposide, with pooled response rates in the range of 10% to 20%.² Various combinations of these agents have been tried to improve upon these response rates. These include 5FU, doxorubicin and mitomycin (FAM); 5FU, doxorubicin and high-dose methotrexate (FAMTX); epirubicin, cisplatin and 5FU (ECF); etoposide, leucovorin and 5FU (ELF). As compared to best supportive care (BSC), combination chemotherapy has yielded significantly superior overall survival (OS) rates.³ However, no single regimen has claimed precedence over the others, and currently there is no universal standard regimen for the treatment of gastroesophageal cancer.⁴ Thus, new treatment protocols are warranted to achieve better disease control while maintaining a tolerable toxicity profile.

The V-325 trial, the largest international phase III trial, showed that adding docetaxel to cisplatin and 5FU improves the time-to-progression (TTP), survival, and response rate in gastric cancer patients, but resulted in increase in toxicity.⁵ Current reports suggest that substituting capecitabine for 5FU, and oxaliplatin for cisplatin, prolongs OS as well as improves safety, quality of life (QOL) and efficacy.⁶

Oxaliplatin is a third-generation diaminocyclohexane platinum compound, which is an alkylating agent inhibiting DNA replication by forming adducts between two adjacent guanines, or guanine and adenine molecules. Adducts of oxaliplatin appear to be more effective than cisplatin adducts with regard to the inhibition of DNA synthesis and it has a more favorable toxicity profile. Capecitabine is an oral fluoropyrimidine that is activated to 5FU preferentially in tumor tissue by a three-step enzymatic conversion culminating with thymidine phosphorylase (TP).⁷ In phase III trials, efficacy data for capecitabine compared favorably with that of parenteral 5FU in the first-line metastatic setting, and resulted in a consistently lower frequency of grade 3 or 4 toxic effects.⁸ Docetaxel has shown promising activity in gastric cancer, both as monotherapy and in combination with other agents.⁹ Moreover, docetaxel shows synergy with capecitabine, as it upregulates TP enzyme in tumor cells.

Encouraged by the high efficacy of DCF and the better safety profile of capecitabine and oxaliplatin when used in place of 5FU and cisplatin, respectively, we designed this study to test the safety and efficacy of the DOX combination.

Patients and Methods

Eligibility criteria included a histologically confirmed metastatic or locally advanced (LA) adenocarcinoma of the stomach or gastroesophageal junction, an age 18 of years or older, an Eastern Cooperative Oncology Group (ECOG) performance status <2, ≥1 unidimensionally measurable lesion ≥1 cm in diameter detected by CT scan or MRI, no prior chemotherapy except in the adjuvant or neoadjuvant setting >6 months prior to study entry and adequate renal, hepatic and hematologic function. Exclusion criteria included a second malignancy, uncontrolled infection, and neuropathy grade >1. Pregnant or lactating women were excluded. All patients gave informed consent prior to enrollment in the study.

Docetaxel was administered as 25 mg/m² followed by oxaliplatin 50 mg/m² on days 1 and 8, with capecitabine 625 mg/m2 twice daily from days 1 to 14, in 21-day cycles. Patients received standard hydration and premedication with corticosteroids and antiemetics. Granulocyte colony-stimulating factor (G-CSF) was used only as secondary prophylaxis once patients had febrile neutropenia or documented neutropenic infection.
Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 3.0). Depending on the severity of side effects, chemotherapy was paused or the dose was reduced. A 20% dose reduction was required based on predefined criteria. Briefly, docetaxel was reduced by 20% in case of the following toxicities: grade 3 or 4 neutropenia lasting more than 7 days (or in presence of fever), second or third incidence of febrile neutropenia despite G-CSF support administered after the first occurrence. The capecitabine dose was reduced by 20% on occurrence of grade 3 or 4 diarrhea or hand/foot syndrome. The oxaliplatin dose was reduced by 20% in case of grade 3 or 4 peripheral neuropathy. Patients were considered assessable for toxicity if they had received a minimum one cycle of treatment.

Before registration, a complete medical history was taken, tumor-related symptoms were recorded and a full body examination was performed. A complete blood cell count (CBC), blood chemistry analyses, electrocardiograph, measurement of creatinine clearance and tumor assessment were carried out in all patients at study entry. Patients were assessed weekly for potential adverse events and disease-related signs and symptoms. Response was evaluated after cycle 3 and cycle 6 according to RECIST criteria.¹⁰ All patients completing a minimum of 3 cycles were eligible for efficacy evaluation. Treatment was continued until completion of 6 cycles, evidence of disease progression, or death or consent withdrawal, whichever occurred earlier. Patients who had ended treatment but had not experienced disease progression were observed every 8 weeks until progressive disease developed using pertinent imaging studies, and every 3 months thereafter. Regardless of response, all patients were followed up until death.

The primary end point was overall response rate (ORR). The primary efficacy end point was the complete response (CR) rate. Patients were considered assessable for response if they had received at least three cycles of treatment. Secondary end points included TTP, OS and toxicity. The TTP was determined from the day of enrollment to the date of any progression, death, or last contact. Patients who had not progressed at the time of the final analysis were censored at the date of their last tumor assessment. OS was calculated from the day of enrollment to death. Patients alive at the final survival analysis were censored using the last contact date. All treated patients were included in the toxicity analyses.

Results

Twenty-one patients were enrolled between March 2007 and February 2009. The primary tumor was located at the gastroesophageal junction in 7 patients and in other parts of the stomach in the remaining 14 patients. One patient had locally advanced tumor without distant metastases and 20 patients presented with metastatic disease, with lymph nodes, the liver, peritoneum and lung as the predominant metastatic sites (Table 1).
In total, 91 cycles of DOX were administered, with a median of three cycles (range 2 to 6) per patient. The median duration of treatment was 12 weeks (range 1 to 18). Dose reductions (including docetaxel in 1/21 patients [5%] and capecitabine in 6/21 patients [29%]) were due to febrile neutropenia in one patient (5%), grade 3/4 diarrhea in five patients (24%), and hand-foot syndrome in one patient (5%). At least one dose reduction was performed in 6/21 patients (29%) due to grade 3/4 toxicity.

The median time until early treatment discontinuation was 9 weeks (range 4 to 9). The main reason for therapy discontinuation was progressive disease (PD) (43%), followed by toxicity (5%) and consent withdrawal (5%). There were no treatment-related deaths.

All 21 patients were assessable for toxicity. Hematologic and non-hematologic adverse events are summarized in Table 2. Treatment was generally well tolerated, with severe adverse events occurring in 7/91 cycles (8%). Overall, 6 patients (29%) experienced grade 3/4 adverse events. The most frequent grade 3/4 hematologic toxicity was febrile neutropenia, occurring in only 5% of patients and 1% of cycles. The most frequent grade 3/4 non-hematologic toxicities possibly or probably related to study treatment were diarrhea (24% of patients, 5% of cycles) and hand-foot syndrome (5% of patients, 1% of cycles). Grade 1-2 toxicities were managed with supportive care (G-CSF, erythropoietin, blood transfusion, antiemetics). For grade 3-4 toxicity, the dose of docetaxel and capecitabine was reduced by 20%.

Nineteen patients (90%) were assessable for response according to RECIST criteria. Two patients were not assessable (one patient was lost to follow-up and one patient stopped therapy after the first cycle due to toxicity), but are included in the response analysis (Table 3). The overall response rate (ORR; complete response + partial response) was 29%. The median TTP was 4.9 months (Figure 1). The median OS for 19 patients was 8.4 months (Figure 2). At the time of the analysis, 5 of the 21 patients enrolled (24%) were alive.

Discussion

There is currently no universal standard regimen for the treatment of gastroesophageal cancer. Meta-analysis has shown the value of combination chemotherapy regimens compared with single agents.¹¹ The addition of docetaxel to cisplatin-5FU resulted in increases in the TTP, OS and QOL, although at the expense of increased toxicity. The V325 study group performed this phase III, randomized trial comparing DCF with the reference regimen CF.5 ORR was higher with DCF (37% vs 25%), which established a role for docetaxel in the treatment of advanced gastroesophageal cancer. However, DCF has significant toxicity and tolerability issues, with greater grade III/IV neutropenia (82% vs 57%), leucopenia (65% vs. 31%) and diarrhea (19% vs. 8%). About 50% of patients on the DCF arm could not complete the scheduled treatment due to toxicity or unwillingness to continue treatment.

Cunningham et al, in a randomized, phase 3 study, showed that for advanced gastroesophageal cancer, oral capecitabine and oxaliplatin are not inferior to infused fluorouracil and cisplatin, respectively, with respect to OS.¹² Response rates were highest in the epirubicin and oxaliplatin plus capecitabine (EOX) group, followed by the epirubicin and cisplatin plus capecitabine (ECX) group. Survival analysis found that the regimen of EOX was superior to ECF with a median survival of 11.2 months versus 9.9 months. EOX had significantly less neutropenia and renal insufficiency when compared with ECF, but more peripheral neuropathy and diarrhea.
With this background, we made an effort to modify the efficacious, albeit toxic DCF regimen, by replacing cisplatin with oxaliplatin and 5FU with capecitabine, to make it more tolerable and easier to administer while maintaining efficacy. The Brown University Oncology Group conducted a phase 1 trial to study this combination of DOX in patients with metastatic esophageal and gastric cancer.¹³ They suggested the regimen of docetaxel 30 mg/m² and oxaliplatin 50 mg/m² day 1 and 8 with capecitabine 750 mg/m² twice daily for 10 days in 21-day cycles. The study enrolled 16 patients with very heterogeneous characteristics: 8 patients had esophageal cancers, of which 2 had squamous histology and 6 were adenocarcinomas; 8 patients had gastric adenocarcinomas. Our study consisted of a more homogenous patient population, consisting only of gastric and gastroesophageal junction adenocarcinomas. The drug regimen in our study was modified slightly for better tolerability and consisted of docetaxel 25 mg/m² and oxaliplatin 50 mg/m2 given on days 1 and 8, with capecitabine 625 mg/m² twice daily from days 1 to 14 in 21-day cycles.

The DOX regimen used the promising activity of all 3 agents against gastroesophageal cancer. We used a lower dose of docetaxel compared to the V325 trial, and also administered it on a weekly schedule. This resulted in significantly less hematologic toxicity and necessitated dose reduction in only one (5%) patient, who developed febrile neutropenia. There were no delays in chemotherapy related to toxicity in this study, and a very low rate of neutropenia was noted despite no prophylactic use of growth factors. In addition, the reduced nausea and nephrotoxicity of oxaliplatin compared to cisplatin, combined with its activity, makes it an excellent option for inclusion in this combination regimen. Also, replacing 5FU with oral capecitabine reduces the hospital stay for prolonged infusions and enables easy administration of this regimen in a day-care setting.
In this single center experience, we present data for the DOX combination in advanced gastric and gastroesophageal cancer. The regimen was well tolerated with a manageable toxicity profile and acceptable efficacy. The most common toxicity in this study was diarrhea related to capecitabine. In the palliative setting of inoperable gastric and gastroesophageal cancer, a chemotherapy regimen that is convenient, less toxic and at the same time efficacious, is the need of the day. Therefore, the DOX regimen is a promising day-care regimen for advanced gastroesophageal cancer.

Author contribution:
Conception and design: Shyam Aggarwal, Gaurav Goel; Provision of study materials or patients: Shyam Aggarwal; Collection and assembly of data: Gaurav Goel, Shyam Aggarwal, Mayank Jauhri, Anita Negi; Data analysis and interpretation: Gaurav Goel, Shyam Aggarwal; Manuscript writing: Gaurav Goel; Final approval of manuscript: Shyam Aggarwal

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