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Keywords:

  • gastroesophageal cancer;
  • metastatic;
  • locally advanced;
  • chemotherapy;
  • docetaxel

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Advanced gastroesophageal cancer patients are often treated with systemic combination chemotherapy. The V-325 study demonstrated that adding docetaxel (D) to a frequently used regimen of cisplatin and 5-fluorouracil (CF) provided benefits with regard to overall survival, response rate, time-to-disease progression, clinical benefit, and health-related quality of life. Although the DCF regimen provides these advantages, it is accompanied by an increase in toxicity compared with the doublet regimen. The toxicity profile of DCF is acceptable only with appropriately selected patients and comprehensive toxicity management strategies. The objective of the current review was to identify trials that investigated modifications to the original DCF regimen to improve its toxicity profile and summarize response rate and toxicities. An attempt was also made to summarize ongoing modifications of the DCF regimen. MEDLINE, major meeting proceedings, and the government clinical trials website were searched until 2007. The modified DCF regimens appear to improve the toxicity profile when compared with the original DCF regimen. The docetaxel-based triplet combinations appear to have a higher response rate than the doublet combinations. Many institutions and cooperative groups continue to study docetaxel-based modifications of the DCF regimen to treat patients with gastroesophageal carcinoma. However, although modified DCF reduces the frequency of severe toxicities previously reported with DCF, considerably more advances are needed to improve the safety, survival, and convenience of patients with advanced gastroesophageal cancer. Cancer 2008. © 2008 American Cancer Society.

Gastric cancer is a significant health problem worldwide, with approximately 930,000 new cases diagnosed and 700,000 deaths attributed to the disease each year.1 In the U.S., the 5-year relative survival rate for individuals with gastric cancer was just 24% during the years 1996 through 2002.2 In Western countries, gastroesophageal cancer commonly remains undiagnosed until it reaches an advanced stage. In the U.S., the stage at diagnosis is localized, locally advanced, metastatic, and unstaged in 23%, 31%, 33%, and 12% of patients, respectively, with corresponding 5-year relative survival rates of 62%, 22%, 3%, and 13%, respectively.2 However, in Japan, gastric cancer mass screening programs have contributed to a situation in which patients are more commonly diagnosed with early‒stage disease and the 5-year survival rate is approximately 60%.3 Although the incidence of cardia (proximal) gastric cancer is increasing in many Western countries, including the U.S.,4, 5 the incidence of noncardia (distal) gastric cancer is generally declining in Western countries. Despite this trend in the West, the incidence of noncardia gastric cancer remains high in many regions, including Japan, China, Eastern Europe, and Central/South America.1, 5

Chemotherapy is the standard treatment for advanced gastroesophageal cancer. A meta-analysis of randomized, controlled trials in patients with advanced gastric cancer (collection of information ending in February 2005) demonstrated that chemotherapy significantly improved the median overall survival (OS) versus best supportive care (hazards ratio [HR] of 0.39; 95% confidence interval [95% CI], 0.28-0.52). In addition, combination chemotherapy was associated with a survival benefit versus single-agent chemotherapy (HR of 0.83; 95% CI, 0.74-0.93) and combination chemotherapy regimens containing 5-fluorouracil (5‒FU), anthracyclines, and cisplatin were associated with a significant survival benefit versus 5-FU and anthracycline regimens without cisplatin (HR of 0.83; 95% CI, 0.76-0.91).6 Despite these findings, the treatment of patients with advanced gastroesophageal cancer remains highly challenging and conventional treatment options remain unsatisfactory in terms of response rate, response duration, toxicity, convenience, and OS benefit. In Europe and North America, commonly used chemotherapy regimens include cisplatin with continuously infused 5-FU (CF), and CF plus epirubicin (ECF). In 2006, the combination of docetaxel, cisplatin, and 5-FU (DCF) was approved for the first-line treatment of advanced gastroesophageal cancer in many parts of the world. This development ended a period of 20 years during which no new chemotherapy agent or regimen gained approval for the treatment of advanced gastroesophageal cancer, particularly in the U.S. The objective of the current review was to summarize the pivotal docetaxel-based trial leading to its approval and review the currently published and ongoing studies of modifications to the DCF regimen. The focus was placed on reviewing the response rate and toxicity of the modified regimens.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A systematic search for all published (MEDLINE search) docetaxel-based combination studies or ongoing trials (available at: www.clinicaltrials.gov/accessed December 15, 2007) was performed to find the information. All studies were collated and summarized for their strengths and weaknesses. In addition, representative ongoing studies were listed.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The V-325 Study

To our knowledge, the activity of docetaxel in gastric cancer was first demonstrated in phase 2 single-agent studies; reported overall response rates were 16% to 24% in the first-line setting and 5% to 21% in previously treated patients, with approximately one‒third of patients on average achieving stable disease.7–16 A phase 2 study was conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the European Institute for Oncology (EIO) to assess the feasibility of docetaxel in combination with cisplatin (DC; docetaxel at a dose of 85 mg/m2 and cisplatin at a dose of 75 mg/m2, administered every 3 weeks) in 48 patients with unresectable and/or metastatic gastric carcinoma who had not been treated previously for advanced disease.17 DC demonstrated reasonable activity, with an objective response rate (ORR) of 56% (complete response rate of 4% and a partial response rate of 52%), and a rate of stable disease of 25%. The toxicity profile was barely acceptable and manageable. Predictably for docetaxel-containing regimens, the main toxicities were hematologic, with grade 3 of 4 (according to the National Cancer Institute Common Toxicity Criteria [version 1.0]) neutropenia reported in 81% of patients and febrile neutropenia in 17%. Other grade 3 toxicities included anemia (32%), fatigue (9%), mucositis (9%), and diarrhea (6%). A subsequent phase 1/2 dose-finding study demonstrated the feasibility of adding a protracted continuous infusion of 5-FU (at a dose of 300 mg/m2/day for 2 weeks) to DC (docetaxel at a dose of 85 mg/m2 and cisplatin at a dose of 75 mg/m2).18 The efficacy and safety profile of the DCF triplet was comparable to that observed for DC in the phase 2 SAKK/EIO study, with an ORR of 51% (intent-to-treat population), and grade 3 or 4 neutropenia and febrile neutropenia reported in 79% and 15% of patients, respectively. On the basis of these results, a 3-arm, randomized, phase 2 study was conducted to compare first-line DCF, DC, and a standard reference regimen (ECF) in 121 patients with measurable unresectable and/or metastatic gastric carcinoma.19 Docetaxel was initially administered at a dose of 85 mg/m2 on Day 1 but after a protocol amendment owing to toxicity after 29 patients had been enrolled, the dose was reduced to 75 mg/m2. The results, with a median follow-up of 27.6 months, demonstrated ORRs of 25.0%, 18.4%, and 36.6% for ECF, DC, and DCF, respectively, and median survival durations of 8.3 months, 11.0 months, and 10.4 months, respectively. DC and DCF were associated with more hematologic toxicity than ECF, with grade 3 neutropenia reported in 76%, 80%, and 59% of patients, respectively. Corresponding rates of febrile neutropenia were 21%, 41%, and 18%, respectively. It is interesting to note that after the protocol amendment, the rate of febrile neutropenia was reduced from 15% to 4% of cycles with DC and from 28% to 12% of cycles with DCF. There was 1 treatment-related death from septicemia in a patient receiving DC. Global health status/quality of life, as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30, improved with ECF and remained stable compared with baseline for both docetaxel-containing regimens. On the basis of these results, the investigators recommended DCF as the superior regimen for further evaluation, particularly in the neoadjuvant setting, in which tumor regression is a priority. However, the toxicity remains a concern and requires active management.

The phase 3 V‒325 study was preceded by a multinational randomized phase 2 study, which took place at approximately the same time as the SAKK/EIO studies. In the phase 2 V‒325 study, first‒line DC (docetaxel at a dose of 85 mg/m2 on Day 1 and cisplatin at a dose of 75 mg/m2 on Day 1) and DCF (docetaxel at a dose of 75 mg/m2 on Day 1, cisplatin at a dose of 75 mg/m2 on Day 1, and 5-FU at a dose of 750 mg/m2/day as a continuous infusion on Days 1-5), both administered every 3 weeks, were compared in 158 patients with metastatic or locally advanced or recurrent gastric or gastroesophageal adenocarcinoma.20 Both regimens were active, with median times‒to‒disease progression (TTPs) of 5.9 months and 5.0 months, respectively, and median OS durations of 9.6 months and 10.5 months, respectively, for DCF and DC. The confirmed ORR was markedly higher in the DCF group compared with the DC group (43% vs 26%), prompting the independent data monitoring committee to recommend further investigation of the DCF regimen in the phase 3 part of the study. Overall, the toxicity profiles of the 2 regimens were considered to be acceptable, with a caution that active management was essential. The most frequent grade 3 adverse events were neutropenia (86% of patients in the DCF group and 87% of patients in the DC group) and gastrointestinal toxicity (56% of patients in the DCF group vs 30% of patients in the DC group).

The phase 3 V‒325 trial was a multinational, multicenter, open-label, randomized trial of first‒line DCF versus CF in patients with metastatic or locally recurrent adenocarcinoma of the gastric or esophagogastric junction.21 A total of 445 patients were randomized and treated with DCF (docetaxel at a dose of 75 mg/m2 and cisplatin at a dose of 75 mg/m2 on Day 1 plus 5-FU at a dose of 750 mg/m2/day as a continuous infusion on Days 1-5) every 3 weeks or CF (cisplatin at a dose of 100 mg/m2 on Day 1 plus 5-FU at a dose of 1000 mg/m2/day as a continuous infusion on Days 1-5) every 4 weeks, with 221 patients and 224 patients, respectively, receiving treatment in each group.

All efficacy endpoints were found to be significantly improved in the DCF arm compared with the CF arm. The median TTP, the primary endpoint, was 5.6 months for DCF and 3.7 months for CF (HR of 1.47; 95% CI, 1.19-1.82; log‒rank P < .001; risk reduction of 32%) (Fig. 1). Median OS, the main secondary endpoint, was 9.2 months for DCF and 8.6 months for CF, a 23% reduction in the risk of death among patients who received DCF (HR of 1.29; 95% CI, 1.0-1.6 [log‒rank P = .02]) (Fig. 1). Survival benefits were also observed for DCF versus CF in terms of the proportion of patients alive at 1 year (40% in the DCF group vs 32% in CF group) or at 2 years (18% in the DCF group vs 9% in the CF group). Response rates were found to be significantly higher in the DCF arm, with overall confirmed response rates of 37% and 25%, respectively, for DCF versus CF (P = .01) (Table 1). It is acknowledged that the difference in the median survival between the 2 arms is not very significant; however, the 2-sided log‒rank P does not only represent the median datapoint but the area between the 2 curves in their entirety.

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Figure 1. (A) Time to disease progression and (B) overall survival among patients with advanced gastric cancer who were treated with docetaxel, cisplatin, and 5-fluorouracil (DCF regimen) or cisplatin and 5-fluorouracil (CF regimen) in the V‒325 Trial.21 (Reprinted with permission from Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 study group. J Clin Oncol. 2006;24:4991-4997.)

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Table 1. Best Overall Response Rates Among Patients with Advanced Gastric Cancer Who Were Treated With DCF or CF in the V325 Trial (Full-Analysis Population)
ParameterNo. of Patients (%)
DCF (n=221)CF (n=224)
  1. DCF indicates docetaxel, cisplatin, and 5-fluorouracil; CF, cisplatin and 5-fluorouracil.

Overall response81 (37)57 (25)
95% CI30.3-43.419.9-31.7
Complete response4 (2)3 (1)
Partial response77 (35)54 (24)
Stable disease67 (30)69 (31)
Progressive disease37 (17)58 (26)
Not assessable36 (16)40 (18)

Grade 3 treatment-emergent adverse events occurred more frequently among patients treated with DCF than among patients treated with CF (69% vs 59%, respectively).21 The principal differences in safety between the 2 groups were related to hematologic events, with grade 3 neutropenia and complicated neutropenia (febrile neutropenia or neutropenic infection) occurring more often in the DCF group compared with the CF group (Table 2). It is interesting to note that the incidence of complicated neutropenia in the DCF group was reduced to 12% with the use of secondary granulocyte–colony-stimulating factor (G-CSF) prophylaxis compared with 27% without G-CSF. Grade 3 diarrhea and neurosensory toxicity were also more common in the DCF group. Importantly, the incidence of death within 30 days of the last infusion was comparable between the 2 groups (10% in the DCF group vs 8% in the CF group), despite the different toxicity profiles of the 2 regimens. The safety issues from the DCF regimen should remain a concern if proper patient selection and continuous patient management are not implemented.

Table 2. Main Grade 3/4 Toxicities in the V-325 Study of DCF Versus CF, Regardless of Relation to Study Treatment21
NCI-CTC Grade 3/4 ToxicityNo. of Patients (%)
DCF (n=221)CF (n=224)
  • DCF indicates docetaxel, cisplatin, and 5-fluorouracil; CF, cisplatin and 5-fluorouracil; NCI-CTC, National Cancer Institute Common Toxicity Criteria (version 1.0).

  • *

    P < .05 in favor of CF.

  • All grades.

Hematologic  
 Neutropenia181 (82)*126 (57)*
 Leukopenia144 (65)*70 (31)*
 Anemia40 (18)57 (25)
 Thrombocytopenia17 (8)30 (13)
 Febrile neutropenia/neutropenia infection63 (29)*27 (12)*
Nonhematologic, treatment emergent
 Gastrointestinal108 (49)106 (47)
 Stomatitis46 (21)61 (27)
 Diarrhea43 (19)*18 (8)*
 Nausea32 (14)38 (17)
 Vomiting32 (14)39 (17)
 Anorexia23 (10)20 (9)
Lethargy41 (19)31 (14)
Infection28 (13)16 (7)
Neurosensory17 (8)*6 (3)*

The impact of chemotherapy on health-related quality of life (HRQoL) is a balance between palliation of disease-related symptoms and treatment-related toxicity. HRQoL is an important consideration for patients receiving palliative treatment for advanced disease. It is necessary to be sure that the efficacy of any noncurative chemotherapy regimen in terms of slowing disease progression and/or prolonging survival is not counterbalanced by a reduction in patient QoL due to treatment-related toxicity. However, HRQoL and clinical benefit have often been overlooked as endpoints in gastric cancer clinical trials. The V‒325 study included a HRQoL analysis, with the primary endpoint of time to 5% definitive deterioration of global health status, measured using the EORTC QLQ-C30 form, compared with baseline.21 A significant difference was observed in favor of DCF versus CF (HR of 1.45; 95% CI, 1.08-1.93 [log-rank P = .01]), demonstrating that the addition of docetaxel to CF resulted in better preservation in global QoL. The median time to the definitive deterioration of global health status was 6.5 months for patients treated with DCF compared with 4.2 months for patients receiving CF. Similarly, in an analysis of clinical benefit, the addition of docetaxel to CF was found to significantly prolong time to definitive worsening of Karnofsky performance status (KPS) by ≥1 category versus baseline (primary clinical benefit endpoint; HR of 1.38; 95% CI, 1.08-1.76 [log-rank P = .009]). The median time to definitive worsening of KPS was found to be 6.1 months for DCF compared with 4.8 months for CF. The results for the majority of other secondary HRQoL analysis, including time to definitive deterioration in social functioning, nausea/vomiting, appetite, pain, and EuroQoL ED-5D thermometer significantly favored the DCF regimen.22 For the secondary clinical benefit analyses, there were nonsignificant trends in favor of DCF in terms of the preservation of weight and appetite; measures of pain-free survival and time to first cancer pain-related opioid intake were comparable in each treatment arm.23

In summary, the results of the V‒325 study demonstrated the superior efficacy of DCF versus CF as first-line treatment for advanced gastric cancer. The toxicities associated with DCF remain a concern. However, the study results document the value of docetaxel in the management of patients with gastroesophageal cancer and also point to the need to develop modifications for the DCF regimen.

Management of DCF-induced Complications

The effective management of docetaxel-associated febrile neutropenia is required to ensure the safety of chemotherapy and to prevent patients from discontinuing treatment early. Recent European and North American guidelines recommend the routine use ofprimary G-CSF prophylaxis when using chemotherapy regimens associated with a risk of febrile neutropenia of ≥20%,24–26 which is within the range associated with docetaxel-based regimens. Indeed, the National Comprehensive Cancer Network (NCCN) lists DCF as an example of a chemotherapy regimen with a high (>20%) risk of febrile neutropenia. Figure 2 summarizes the latest NCCN recommendations for prophylaxis for febrile neutropenia after chemotherapy.26

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Figure 2. National Comprehensive Cancer Network guidelines regarding prophylaxis for febrile neutropenia after chemotherapy.26 CSF indicates colony stimulating factor. (Reprinted with permission from The NCCN (1.2007) Myeloid Growth Factors Clinical Practice Guidelines in Oncology. © National Comprehensive Cancer Network, 2007. Available at URL: http://www.nccn.org. Accessed December 2007. To view the most recent and complete version of the guideline, go online to www.nccn.org. These Guidelines are a work in progress that will be refined as often as new significant data becomes available. The NCCN Guidelines are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN guideline is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These Guidelines are copyrighted by the National Comprehensive Cancer Network. All rights reserved. These Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN.)

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The results of the V‒325 study support the benefits of G-CSF use in conjunction with the DCF regimen; the administration of secondary prophylactic G-CSF to patients in the DCF group reduced complicated neutropenia to the same rate as that observed in the CF group (12%). Primary prophylactic G-CSF should be strongly considered to reduce the risk of neutropenia associated with the DCF regimen. Further support for the benefits of administering primary prophylactic G-CSF in conjunction with high-risk chemotherapy is provided by phase 3 studies in patients with breast cancer. Significant reductions in the incidence of hematologic toxicity-related events including febrile neutropenia, neutropenia-associated hospitalization, and the use of intravenous anti-infectives have been observed among patients receiving docetaxel-based chemotherapy with primary prophylactic G-CSF compared with those receiving docetaxel-based chemotherapy without primary prophylactic G-CSF.27–29 The combination of pegfilgrastim and ciprofloxacin is reported to be particularly effective in this setting.29

Modifications of the DCF Regimen

Although DCF has become a new reference regimen for the treatment of advanced gastroesophageal cancer, research is already underway to further improve its tolerability. Several variations of DCF have either been reported or are currently under investigation, with different administration schedules, alternative platinum and fluoropyrimidine components, and the addition of biologic agents.

Preliminary data suggest that modification of the standard DCF schedule may yield a regimen with an improved safety profile, without compromising the efficacy of the regimen. Weekly docetaxel in combination with cisplatin and 5-FU (wDCF; docetaxel at a dose of 30 mg/m2 on Days 1 and 8, cisplatin at a dose of 60 mg/m2 on Day 1, and 5-FU at a dose of 200 mg/m2 per day as a continuous infusion for 21 days, every 3 weeks) or in combination with capecitabine (wDX; the same schedule of docetaxel combined with capecitabine at a dose of 1600 mg/m2/day on Days 1-14, every 3 weeks) has been investigated as first-line therapy in 106 patients with metastatic gastric or esophageal carcinoma (50 patients in the wDCF group and 56 patients in the wDX group).30 With a median follow-up of 14.6 months, the median progression‒free survival (PFS) and OS durations were 5.9 months and 12.8 months, respectively, for wDCF and 4.2 months and 10.1 months, respectively, for wDX. The confirmed ORR was 49% (95% CI, 35%-63%) in the wDCF group and 26% (95% CI, 16%-39%) in the wDX group. It is interesting to note that grade 3 diarrhea was reported in 10% and 7%, respectively, of patients and febrile neutropenia/neutropenic infection in 4% and 2%, respectively, of patients in the wDCF and wDX groups. Notably, 23 of 24 patients with advanced disease underwent secondary surgical resection and complete surgical resections (R0) were achieved in 87%. Another study by Orditura et al using docetaxel plus capecitabine resulted in a 21% response rate and the safety profile was determined to be acceptable.31 One may argue that combinations that do not include a platinum compound tend to have a lower response rate, with the understanding that response is important for the palliation of symptoms but may not translate into a survival advantage.

The GASTRO-TAX-1 trial was conducted to investigate a split-dose regimen of docetaxel, cisplatin, leucovorin, and 5-FU in chemotherapy-naive patients with nonresectable esophagogastric adenocarcinomas.32 A total of 60 patients received docetaxel and cisplatin on Days 1, 15, and 29 and leucovorin plus 5-FU on Days 1, 8, 15, 22, 29, and 36, every 7 weeks. The initial starting doses were docetaxel, 50 mg/m2; cisplatin, 50 mg/m2; leucovorin, 500 mg/m2; and 5-FU, 2000 mg/m2 as a continuous infusion over 24 hours; however, because dose reduction to <80% of the initial dose was necessary in 80% of the first 15 patients treated, the doses were changed to docetaxel, 40 mg/m2; cisplatin, 40 mg/m2; leucovorin, 200 mg/m2; and 5-FU, 2000 mg/m2 as a continuous infusion over 24 hours, administered using the same schedule. Grade 3 neutropenia was reported to occur in 23% of patients, with febrile neutropenia in 5%. Other grade 3 adverse events included diarrhea (20%), nausea (8%), emesis (8%), and fatigue (20%). The ORR was 47% (95% CI, 33.3%-61.4%), and after a median follow-up of 25.5 months, the median TTP was 9.4 months and the median OS was 17.9 months. Complete surgical resection was achieved in 20 of 23 patients (87%) with locally advanced disease. It is acknowledged that one cannot make claims of high efficacy based on these trials, but the safety profile certainly appears to be favorable.

Activity and a favorable safety profile have been reported for low-dose docetaxel in combination with cisplatin and 5-FU.33 Forty-seven patients with metastatic gastric cancer who had not received prior chemotherapy were treated with docetaxel at a dose of 50 mg/m2 and cisplatin at a dose of 80 mg/m2 on Day 1, and 5-FU at a dose of 1200 mg/m2 per day on Days 1 through 3, every 3 weeks, for a median of 4 cycles. A partial response was observed in 17 of 42 evaluable patients (40%; 95% CI, 26%-55%); the median TTP was 4.6 months and the median OS duration was 9.7 months. The most common grade 3 nonhematologic toxicities were stomatitis (21%) and syncope (6%); other grade 3 nonhematologic toxicities occurred in <5% of patients. Grade 3 neutropenia was reported in 68% of patients, with febrile neutropenia/neutropenic infection reported in 26%.

Substitution of Cisplatin with Oxaliplatin

The diaminocyclohexane platinum compound oxaliplatin has demonstrated in vitro activity in human gastric cancer cell lines.34, 35 Similar to cisplatin, oxaliplatin forms platinum–DNA adducts, which inhibit DNA synthesis and repair.36 However, oxaliplatin has a wider spectrum of antitumor activity than cisplatin37 and is active in cell lines with acquired cisplatin resistance as well as in tumor types with intrinsic cisplatin resistance.38 Oxaliplatin and cisplatin also differ in terms of toxicity profile. Oxaliplatin is commonly associated with sensory neuropathy, comprised of transient, acute cold-related sensory neuropathy and cumulative, chronic, dose-limiting sensory neuropathy that generally resolve over time.39 Cisplatin is associated with dose-limiting nephrotoxicity; peripheral neuropathy; and dose-dependent, irreversible, ototoxicity.34 Therefore, although oxaliplatin is a reasonable alternative platinum agent, cumulative neuropathy remains a concern.

The REAL-2 study (analog substitutions to reduce toxicity)

The randomized ECF for advanced and locally advanced gastroesophageal cancer 2 (REAL-2) study investigated the potential for substituting oxaliplatin for cisplatin and oral capecitabine for intravenous (iv) 5-FU in the conventional ECF regimen.40 The study had a 2-by-2 factorial design and patients were randomized to receive ECF; the combination of epirubicin, cisplatin, and capecitabine (ECX); the combination of epirubicin, oxaliplatin, and /5-FU (EOF); or the combination of epirubicin, oxaliplatin, and capecitabine (EOX). For each regimen, doses were epirubicin at a dose of 50 mg/m2 every 3 weeks, cisplatin at a dose of 60 mg/m2 every 3 weeks, oxaliplatin at a dose of 130 mg/m2 iv every 3 weeks, 5-FU at a dose of 200 mg/m2 iv as continuous infusion daily, and capecitabine at a dose of 625 mg/m2 orally twice daily, every day, for 8 cycles. The primary endpoint was OS and the study was powered to demonstrate the noninferiority of capecitabine over 5-FU and of oxaliplatin over cisplatin. A total of 1002 patients were randomized and, after a median follow-up duration of 17.1 months, the primary endpoint had been met for both the fluoropyrimidine and platinum comparisons.39 The median OS was 10.9 months for patients who received capecitabine (ECX or EOX) compared with 9.6 months for patients who received 5-FU (ECF or EOF) (HR of 0.86; 95% CI, 0.75-0.99), and was 10.4 months for patients who received oxaliplatin (EOX or EOF) compared with 10.1 months for patients who received cisplatin (ECF or ECX) (HR of 0.92; 95% CI, 0.80-1.05).40 The incidences of grade 3 nonhematologic toxicities were 36%, 42%, 33%, and 45%, respectively in the ECF, ECX, EOF, and EOX arms, and grade 3 neutropenia was significantly less common in the 2 oxaliplatin-containing treatment arms compared with the comparator arm (42% in ECF and 30% in EOF [P = .008]; 51% in ECX [P = .043]; and 28% in EOX [P = .001]).

These data demonstrate that the fluoropyrimidine and platinum components of ECF may be substituted with capecitabine and oxaliplatin, respectively, with no decrease in efficacy noted.

The combination of docetaxel and oxaliplatin

There is a rationale for combining docetaxel and oxaliplatin based on the activity of both agents in gastric cancer and in combination with infusional 5-FU, and their distinct and complementary mechanisms of action, lack of cross-resistance, and different toxicity profiles. The combination of docetaxel and oxaliplatin has been investigated in several recent phase 2 studies.40–45 A study by the U.S. Oncology Group assessed first-line treatment with docetaxel and oxaliplatin (docetaxel at a dose of 60 mg/m2 iv over 1 hour on Day 1 followed by oxaliplatin at a dose of 130 mg/m2 iv over 2 hours on Day 1, every 3 weeks) in 71 patients with metastatic adenocarcinoma of the stomach and/or gastroesophageal junction.41 The combination of docetaxel and oxaliplatin achieved an ORR of 36% and responses lasted a median duration of 5.6 months. The median OS and PFS durations were 8.5 months and 4.3 months, respectively. The most common nonhematologic adverse events were vomiting (17%), nausea (16%), dehydration (13%), diarrhea (13%), and fatigue (13%). Grade 3 neutropenia was reported in 70% of patients, with febrile neutropenia reported in 7% and thrombocytopenia in 7%. The combination of docetaxel and oxaliplatin has also demonstrated activity in patients with advanced gastric cancer who have developed disease progression while receiving 5-FU-based therapy. In a study of 38 patients, docetaxel at a dose of 75 mg/m2 on Day 1 and oxaliplatin at a dose of 80 mg/m2 on Day 2, every 3 weeks, achieved an ORR of 10.5% and a stable disease rate of 47.3%. The median TTP was 4.0 months and the median OS was 8.1 months. Grade 3 toxicities were neutropenia (26.3%), asthenia (15.7%), nausea/vomiting (15.7%), and neurotoxicity (2.6%). There were no cases of febrile neutropenia reported and no other grade 3 hematologic toxicities.42 In another phase 2 study, doublet therapy with docetaxel at a dose of 80 mg/m2 plus oxaliplatin at a dose of 100 mg/m2 on Day 1 every 3 weeks, with G-CSF at a dose of 5 μg/kg/day on Days 2 through 6, was investigated in 36 patients with metastatic or locally advanced esophagogastric cancer.43 A confirmed response was reported in 13 of 36 patients (36%), with a median TTP of 5.6 months and a median OS duration of 9.8 months. The main toxicity was hematologic and grade 3 neutropenia and anemia each occurred in 16.6% of patients.

A small study (16 patients) has assessed the combination of docetaxel (50 mg/m2 over 1 hour) with modified FOLFOX6 (oxaliplatin at a dose of 85 mg/m2 iv over 2 hours plus 5-FU at a dose of 400mg/m2 bolus and 3000 mg/m2 iv over 48 hours plus leucovorin at a dose of 400 mg/m2 iv over 2 hours) in patients with locally advanced or metastatic gastric cancer. This regimen was well tolerated and achieved an ORR of 44%, including 1 complete and 6 partial responses.44 Docetaxel in combination with modified FOLFOX (docetaxel at a dose of 50 mg/m2 on Day 1 plus oxaliplatin at a dose of 85 mg/m2 in combination with leucovorin at a dose of 200 mg/m2 plus 5-FU at a dose of 2600 mg/m2 iv over 24 hours, every 2 weeks [FLOT regimen]) achieved an ORR of 51% in a study of 59 patients with untreated locally advanced or metastatic cancer of the stomach or gastroesophageal junction.45 The median PFS was 5.3 months, the median OS was 11.3 months, and the 6-month survival rate was 75%. The main grade 3 adverse events were neutropenia (46.3%), leukopenia (22.2%), and diarrhea (14.8%). Febrile neutropenia was reported in 3.7% of patients. Preliminary results have also been reported for an ongoing phase 1/2 study of docetaxel in combination with 5-FU and oxaliplatin (d-FOX regimen).46 A total of 41 patients with untreated advanced gastric or gastroesophageal cancer have been enrolled to receive docetaxel (at a starting dose of 20 mg/m2 with dose escalation in 2.5‒mg/m2 increments to find the maximum tolerated dose [MTD]) plus oxaliplatin at a dose of 85 mg/m2 and 5-FU at a dose of 2200 mg/m2 iv over 48 hours on Day 1 for the first 2 weeks of a 4-week cycle. The MTD for docetaxel had not been reached after 4 weeks of treatment (the dose level was 50 mg/m2 at the time of last follow‒up). The d-FOX regimen was found to be well tolerated, with no neutropenic infection or febrile neutropenia reported during the first cycle; the most common grade 3 toxicities were neutropenia (7.3%) and anemia (26.8%).46

The combination of docetaxel at a dose of 60 mg/m2 and irinotecan at a dose of 150 mg/m2 on Day 1, plus oxaliplatin at a dose of 85 mg/m2 on Day 2, has been evaluated in a phase 2 study in patients with metastatic gastric or gastroesophageal junction cancer.47 A response rate of 50% was observed in 40 patients, with a median OS of 11.5 months. The most notable toxicity was grade 3 neutropenia, which occurred in 48% of patients and 3 patients had 4 episodes of febrile neutropenia. To further investigate the utility of the docetaxel and oxaliplatin combination, the randomized phase 2 GATE study has been initiated to investigate 3 docetaxel and oxaliplatin regimens in patients with advanced gastric or gastroesophageal junction adenocarcinoma. Approximately 270 patients who have not received prior palliative chemotherapy will be randomized to treatment with docetaxel and oxaliplatin; docetaxel, oxaliplatin, leucovorin, and 5-FU; or docetaxel, oxaliplatin, and capecitabine. The primary endpoint is TTP and secondary endpoints include toxicity, ORR, and OS.48, 49 A multicenter, nonrandomized phase 2 study is also currently ongoing to assess the combination of docetaxel and oxaliplatin plus bevacizumab in patients with locally advanced, unresectable, or metastatic gastric or gastroesophageal junction cancer. The target accrual is 38 patients and the primary study endpoint is TTP.50

There is also potential for the docetaxel and oxaliplatin combination in the neoadjuvant setting. In a planned, nonrandomized, phase 2 EORTC study, patients with locally advanced gastric or gastroesophageal junction adenocarcinoma will receive preoperative treatment with docetaxel, oxaliplatin, and 5-FU followed by concomitant oxaliplatin and 5-FU plus radiotherapy and then surgery.51 Another ongoing, nonrandomized phase 2 study will assess the feasibility of neoadjuvant combination chemotherapy with docetaxel and oxaliplatin, floxuridine (an analog of 5-FU), and leucovorin in patients with previously untreated, resectable esophageal cancer. The target accrual is 34 patients and the primary study endpoint is the pathologic complete response rate.52

Capecitabine is an oral prodrug of 5-FU that can potentially increase the convenience of chemotherapy by eliminating the need for lengthy iv 5-FU infusion. As described earlier, the REAL-2 study demonstrated the noninferiority of substituting capecitabine for 5-FU in the ECF regimen.40 Small phase 2 studies have also demonstrated the feasibility of administering capecitabine in combination with docetaxel, with response rates ranging from 39% to 55% (with occasional exceptions)30, 31 and an acceptable toxicity profile comprising, primarily, neutropenia, febrile neutropenia, diarrhea, nausea, stomatitis, and hand–foot syndrome.30, 53–57 Evans et al have further modified the DCF regimen by substituting cisplatin with carboplatin to reduce neurotoxicity, while increasing the convenience of the regimen by substituting capecitabine for 5-FU.58 The docetaxel, carboplatin, and capecitabine regimen was found to be well tolerated in this phase 2 study, with grade 3 neutropenia and grade 3 diarrhea, nausea/vomiting, and dehydration being the most notable toxicities. Responses were observed in 48% of patients, with complete responses noted in 3 patients; the median OS was 8 months (95% CI, 5.5 months-13 months) and the 1-year survival rate was 36%.

S-1

S-1 is a rationally designed oral fluoropyrimidine. This novel agent consists of the 5-FU prodrug tegafur combined with 2 enzyme inhibitors: a dihydropyrimidine dehydrogenase inhibitor, which increases plasma concentrations of 5-FU and may decrease toxicity (hand–foot syndrome, neurotoxicity, and cardiotoxicity) by reducing catabolites that are implicated, and an orotate phosphoribosyl transferase inhibitor, which decreases the conversion of 5-FU to fluoropyrimidine monophosphate, which is known to promote diarrhea and therefore may decrease the frequency and/or severity of diarrhea. S-1 has been available for the treatment of gastric cancer in Japan since 1999, having demonstrated high response rates and a favorable toxicity profile.59, 60

Several international phase 3 studies are currently ongoing to investigate S-1 as monotherapy and in combination with other agents. The combination of docetaxel and S-1 (docetaxel at a dose of 40 mg/m2 iv on Day 1 and S-1 at a dose of 80 mg/m2/day on Days 1-14, every 3 weeks) was investigated in a phase 2 study of 48 patients with advanced or recurrent gastric adenocarcinoma who had received up to 1 previous chemotherapy regimen. The ORR was 56% (all partial responses) and 38% of patients had achieved stable disease. The median OS was 14.3 months and the median TTP was 7.3 months.61 The combination of docetaxel and S-1 was found to be well tolerated; the most common grade 3 toxicities were neutropenia (58%), leukopenia (42%), anorexia (15%), febrile neutropenia (8%), anemia (8%), stomatitis (8%), and nausea (6%) and no grade 4 nonhematologic toxicities were reported.60 The S-1 plus taxotere versus S-1 alone in advanced gastric cancer randomized trial (START) is a large phase 3 trial that was recently initiated in Japan and Korea and will compare the combination of docetaxel and S-1 with S-1 alone in patients with inoperable or recurrent gastric or gastroesophageal cancer.50 A total of 628 patients are projected to be enrolled in this trial, which will examine OS as the primary endpoint. However, to our knowledge, the efficacy of S-1 in patients with advanced gastroesophageal cancer has yet to be established.

Biologic Agents and Docetaxel-based Therapy

Several phase 2 trials are currently underway to investigate various regimens of docetaxel in combination with biologic agents, including docetaxel and bevacizumab; docetaxel, oxaliplatin, and bevacizumab; docetaxel, cisplatin, and sorafenib; docetaxel plus oxaliplatin and cetuximab; and docetaxel and imatinib. Results from a small study of docetaxel plus bevacizumab have been presented.62 A total of 20 patients with advanced gastric or esophageal cancer received docetaxel at a dose of 35 mg/m2 on Days 1, 8, and 15 plus bevacizumab at a dose of 5 mg/kg on Days 1 and 15, every 4 weeks. Interim response data for 15 patients demonstrated a partial response in 4 patients (27%) and stable disease in another 5 patients (33%). Grade 3 adverse events included anemia (15%), fatigue (15%), neutropenia (10%), gastrointestinal bleeding (15%), and arterial thrombosis (10%), with the latter 2 events likely to be related to bevacizumab.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The DCF regimen has become a new chemotherapeutic treatment option for patients with advanced gastric and gastroesophageal cancer, supported by the results of the V‒325 trial. The addition of docetaxel to the CF combination achieved significant improvements in TTP, OS, 1-year and 2-year survival, and ORR. QoL and clinical benefit were found to be favorable for DCF and were not compromised by the higher toxicity that accompanies the more active triplet regimen. Secondary prophylactic G-CSF reduced the incidence of complicated neutropenia in the DCF treatment arm to the same rate as that observed in the CF treatment arm; this observation is consistent with recent guidelines that recommend that patients should receive primary G-CSF prophylaxis in conjunction with chemotherapy regimens that are associated with a high risk of febrile neutropenia. However, DCF is associated with substantial toxicity. Ongoing research suggests that further improvement of the safety of the DCF regimen may be achieved by altering the treatment schedule, substituting cisplatin with oxaliplatin, and substituting a continuous infusion of 5-FU with an orally administered fluoropyrimidine. These modest improvements experienced by our patients are clearly not sufficient and we need to continue to strive to improve the efficacy, safety, and convenience of the treatment. The role of biologic agents in gastroesophageal cancer therapy remains to be defined but will be a logical next step for investigation. Finally, an active and safe combination regimen might produce dramatic benefit in the preoperative setting and should be investigated further.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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