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Docetaxel, Cisplatin, and Fluorouracil; Docetaxel and Cisplatin; and Epirubicin, Cisplatin, and Fluorouracil As Systemic Treatment for Advanced Gastric Carcinoma: A Randomized Phase II Trial of the Swiss Group for Clinical Cancer Research

Arnaud D. Roth, Nicola Fazio, Roger Stupp, Stephen Falk, Jürg Bernhard, Piercarlo Saletti, Dieter Köberle, Markus M. Borner, Kaspar Rufibach, Rudolf Maibach, Martin Wernli, Martin Leslie, Robert Glynne-Jones, Lukas Widmer, Matthew Seymour, Filippo de Braud

From the Oncosurgery Unit, Geneva University Hospital, Geneva; Multidisciplinary Oncology Center, University Hospital (CHUV), Lausanne; Swiss Group for Clinical Cancer Research Coordinating Center; Department of Medical Oncology, Inselspital, Bern; Oncology Institute of Southern Switzerland, Ospedale Civico, Lugano; Division of Oncology, Department of Medicine C, Kantonspital, St Gallen; Kantonspital Aarau, Aarau; Institute of Medical Oncology, Triemlispital, Zurich, Switzerland; Department of Medicine, European Institute of Oncology, Milan, Italy; Bristol Oncology Center, Bristol; St Thomas Hospital, London; Mount Vernon Hospital, Middlesex; and Cookridge Hospital, Leeds, United Kingdom

Address reprint requests to Arnaud D. Roth, MD, Department of Oncosurgery, Geneva University Hospital, 24 Micheli-Du-Crest, CH-1211 Geneva 14, Switzerland; e-mail: arnaud.roth{at}sim.hcuge.ch

	ABSTRACT

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Purpose: This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy.

Patients and Methods: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status 1, and adequate hematologic, hepatic, and renal function randomly received eight 3-weekly cycles of ECF (epirubicin 50 mg/m² on day 1, cisplatin 60 mg/m² on day 1, and fluorouracil [FU] 200 mg/m²/d on days 1 to 21), TC (docetaxel initially 85 mg/m² on day 1 [later reduced to 75 mg/m² as a result of toxicity] and cisplatin 75 mg/m² on day 1), or TCF (TC plus FU 300 mg/m²/d on days 1 to 14). Study objectives included response (primary), survival, toxicity, and quality of life (QOL).

Results: ORR was 25.0% (95% CI, 13% to 41%) for ECF, 18.5% (95% CI, 9% to 34%) for TC, and 36.6% (95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 months for ECF, TC, and TCF, respectively. Toxicity was acceptable, with one toxic death (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%; TCF, 57%; ECF, 34%). Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens.

Conclusion: Time to response and ORR favor TCF over TC for further evaluation, particularly in the neoadjuvant setting. A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed.

	INTRODUCTION

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Despite a declining incidence, gastric carcinoma is a leading cause of cancer death in the Western world.¹ Surgery remains the treatment of choice for curing early disease. Unfortunately, most patients present with unresectable stage III to IV disease, for which treatment options have been limited. Over the last decade, new chemotherapy regimens have been developed for the treatment of advanced gastric cancer, including epirubicin-cisplatin plus continuous-infusion fluorouracil (ECF).² Compared with fluorouracil (FU) -doxorubicin-methotrexate in a phase III randomized trial, ECF yielded a superior overall response rate (ORR; 21% v 45%, respectively), superior median time to progression (TTP; 3.4 v 7.4 months, respectively), and better overall survival (OS; 5.7 v 8.9 months, respectively),³ leading the investigators to propose ECF as a standard therapy.^3,4

More recently, agents belonging to the taxane, camptothecin, and platinum classes have been studied as systemic therapy for gastric cancer.^5,6 In particular, docetaxel (60 to 100 mg/m²) monotherapy yielded response rates of 17% to 24% in phase II studies.^7-9 On the basis of promising results from our phase II trial of docetaxel plus cisplatin (TC) in gastric carcinoma,¹⁰ a subsequent phase I to II trial was conducted to investigate the benefits of adding FU to TC (TCF).¹¹ Both regimens seemed active in gastric cancer; response rates were 56% for TC (n = 48) and 51% for TCF (n = 41).^10,11 Accordingly, we initiated a three-arm randomized phase II study with TC, TCF, and ECF in metastatic gastric cancer patients aimed at reproducing these data and determining whether TC or TCF is the more appropriate regimen for comparison against ECF in a future randomized phase III trial.

	PATIENTS AND METHODS

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Patient Selection and Treatment
Chemotherapy-naïve patients with bidimensionally measurable, unresectable, metastatic, or locally advanced gastric adenocarcinoma were enrolled. Other inclusion criteria included WHO performance status 1; adequate blood counts (hemoglobin 10 g/L, WBC count of 4,000/µL, and platelets of 100,000/µL); creatinine clearance 60 mL/min; adequate liver function tests (bilirubin < 1.25x the upper limit of normal and AST/ALT < 2.5x then upper limit of normal); no history of anaphylaxis; and no peripheral neuropathy grade 1. The trial was approved by the local ethics committees in all participating institutions. All patients provided written informed consent.

Patients were randomly assigned at the Swiss Group for Clinical Cancer Research Coordinating Center before treatment and stratified by center, liver involvement, and performance status. Patients received 3-weekly cycles of ECF (epirubicin 50 mg/m² intravenous [IV] bolus on day 1, cisplatin 60 mg/m² 4-hour IV infusion on day 1, and FU 200 mg/m²/d continuous IV infusion on days 1 to 21), TC (docetaxel 85 mg/m² 1-hour IV infusion on day 1 and cisplatin 75 mg/m² 4-hour IV infusion on day 1), or TCF (TC plus FU 300 mg/m²/d continuous IV infusion on days 1 to 14) for up to eight cycles or until disease progression, unacceptable toxicity, or consent withdrawal.

All patients received the following supportive medication: 3 L/d hyperhydration; dexamethasone 8 mg orally administered 12 and 6 hours before docetaxel infusion and 8 mg twice daily for 4 days after infusion; and 5-hydroxytryptamine-3 inhibitors as emesis prophylaxis. Use of hematologic growth factors was allowed and documented. After enrollment of the first 29 patients (March 19, 2001), the protocol was amended to reduce the docetaxel dose from 85 mg/m² to 75 mg/m² in both docetaxel-containing arms because of an unexpectedly high incidence of febrile neutropenia.

Treatment could be delayed for up to 2 weeks to allow toxicities to resolve; delays of more than 2 weeks necessitated treatment withdrawal. A 15-mg/m² dose reduction of docetaxel or epirubicin was mandatory for prolonged (> 7 days) grade 4 neutropenia or thrombocytopenia, grade 2 liver toxicity, or grade 3 skin toxicity. For grade 2 neurotoxicity, docetaxel and cisplatin doses were reduced by 15 mg/m². Cisplatin was reduced or stopped if creatinine clearance was less than 60 mL/min or less than 40 mL/min, respectively. The FU dose was reduced by 50 mg/m²/d and 100 mg/m²/d for grade 2 and 3, respectively, diarrhea, mucositis, or palmar-plantar syndrome. Treatment was stopped and the patient was withdrawn for persistent grade 3 liver toxicity, anaphylaxis, or fluid retention; grade 3 neuropathy; grade 4 skin toxicity; or a recurrent toxicity despite dose reductions.

Response, Toxicity, and Quality-of-Life Assessments
Responses were assessed (using WHO criteria) every 6 weeks by computed tomography scans, chest x-ray, or magnetic resonance imaging and were confirmed 4 weeks later. All responses were confirmed by an independent panel of radiologists and an oncologist. After completion or withdrawal of treatment, disease status was assessed every 3 months.

Toxicities were assessed using National Cancer Institute of Canada-Clinical Trials Group expanded common toxicity criteria. Febrile neutropenia was defined by fever 38.1°C and grade 4 neutropenia.

All randomly assigned patients were asked to complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30; version 3.0)¹² at baseline and on day 1 of cycles 2, 4, and 6 before evaluations and treatment. Regarding docetaxel and cisplatin toxicity, two specific items for numbness/paresthesia in hands and feet were added to the EORTC QLQ-C30. Global indicators for treatment burden and coping effort were also added.^13,14 All scales were linearly transformed to range from 0 to 100. For comparison, 0 and 100 represented the worst and best, respectively, possible conditions. This was with permission from the EORTC Quality of Life (QOL) Unit but was not consistent with the QLQ-C30 Manual. The questionnaire was completed with the following item measuring subjectively meaningful change between baseline and the beginning of cycle 2 (ie, after 3 weeks): "Please try to remember how you felt before you started therapy and compare it with the way you feel now." Patients were asked to choose one of seven verbal categories ranging from "very much worse" to "very much better."

Statistical Analyses
The primary objective was to determine, on the basis of ORR, whether TC or TCF was more promising for comparison against ECF in a subsequent phase III trial. The protocol allowed for conversion into a randomized two-arm phase III study, if deemed appropriate. The randomized phase II trial approach of Simon et al¹⁵ was applied. Thirty-seven patients were required per docetaxel arm to detect an absolute difference in ORR of 15% between TCF and TC with 90% probability. An equal number of patients was planned for the ECF arm. Overall, 121 patients were accrued to ensure maintenance of statistical power.

Time to treatment failure (TTF) was measured from random assignment to treatment withdrawal from any cause, TTP was measured from random assignment to progression or death without progression, and OS was measured from random assignment to death. Median time to treatment response (TTR) was defined post hoc as the time from treatment start to the first observation of partial response or complete response and was calculated for patients with one partial response. Early progressive disease was defined as disease progression during cycles 1 or 2. CIs for response rates were calculated by Sterne's method.

Indicators of QOL were descriptive and evaluated as changes from baseline. The two items for numbness/paresthesia were averaged (average internal consistency under treatment: = .82). Effects of treatment, time, and treatment-time interactions were longitudinally analyzed by a nonparametric mixed-effects model using all available data within the prefailure observation period. For all measures, a 10-point change from baseline was defined as a clinically substantial change.¹⁶ The observed changes between baseline and cycle 2 were compared with the rating of subjective change within patients.

All tests were two sided. No adjustment was made for multiple testing. Reported P values have descriptive value only.

	RESULTS

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Patients and Treatment
Of 121 patients randomly assigned between September 1999 and July 2003, two were not treated (renal failure, n = 1; and ineligibility, n = 1) and were excluded. Another patient received two cycles of TCF before being considered ineligible but was included in the analyses.

Patient characteristics were generally well balanced; patients in the ECF arm had lost less weight in the 3 months preceding random assignment, and fewer had undergone previous gastrectomy (Table 1). Medians of 5.5, 5.0, and 4.0 cycles of EFC, TC, and TCF, respectively, were received. Median treatment duration was longer for ECF-treated patients, with more patients completing eight cycles of treatment (Table 2).

Treatment delays of more than 7 days occurred more frequently in ECF cycles, mainly because of prolonged hematotoxicity. Dose reductions were necessary in more TCF cycles and patients, and FU was the drug reduced most often (ECF: 19%, TCF: 32%); however, median doses over all cycles were close to the prescribed schedule (Table 2). More patients refused to continue their chemotherapy in the TCF arm, but 50% of these patients did so after having received six cycles. Hematologic growth factors were required more often with docetaxel-based therapy (Table 2).

Efficacy End Points
The ORR was 25.0%, 18.4%, and 36.6% with ECF, TC, and TCF, respectively (Table 3). Eight patients were excluded as responders because radiologic evidence was not available for central review (Table 3). Early progressive disease was observed in 15%, 15%, and 12% of ECF, TC, and TCF patients, respectively. Nine patients (five, one, and three patients in ECF, TC, and TCF arms, respectively) did not complete two cycles (nonresponders).

Toxicity
Grade 3 to 4 neutropenia occurred in 34% of ECF cycles and approximately half of docetaxel-containing cycles (Table 4). Febrile neutropenia was more frequent with TCF. After the protocol amendment to reduce the docetaxel dose from 85 to 75 mg/m², the febrile neutropenia incidence decreased from 15% to 4% for TC and from 28% to 12% for TCF. One treatment-related death occurred (after septicemia in a TC-treated patient).

QOL
Of all expected QOL forms before treatment failure, 120 (100%) were received at baseline, and 175 (71%) were received under treatment. Timing deviations between QOL assessment and day 1 of cycle were balanced; the median difference across all assessments and arms was 0 days (25% to 75% range = 7 days).

At baseline, patients reported considerably impaired global health status/QOL and emotional functioning and much effort to cope with their disease (Table 5). Fatigue and appetite loss were the most prominent symptoms.

Treatment burden increased over time (P < .05), with substantial changes with TC (cycle 4: n = 15; median change = –16.7) and TCF (cycles 2/4/6: n = 20/16/15; median changes = –16.7). Numbness/paresthesia also increased (time effect: P < .0001), with substantial changes at cycle 6 with TC and TCF (Table 6). In the remaining QOL measures, there was no marked effect by randomly assigned treatment or time.

The comparison of observed and subjective (patient-estimated) changes between baseline and cycle 2 varied among the measures. For global health status/QOL, a median improvement of 8.3 (n = 18) was associated with "moderately/very much better." For treatment burden, a median worsening of –16.7 (n = 30) was associated with "a little worse/about the same/a little better."

	DISCUSSION

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In this randomized phase II study, we evaluated the safety and efficacy of two docetaxel-containing regimens in reference to the standard ECF combination in advanced gastric cancer as previously established by British investigators.^10,11 TCF was associated with an increased ORR compared with TC, and OS was comparable. Thus, according to the randomized phase II design proposed by Simon et al,¹⁵ if a randomized phase III trial were to be conducted, the TCF regimen should be preferred over TC for comparison with ECF. An additional finding was that the TCF regimen resulted in a shorter TTR versus ECF (median TTR, 1.6 v 3.0 months, respectively). This suggests that TCF may also be an effective treatment option in the neoadjuvant setting, where rapid tumor reduction before curative surgery is essential, in line with previous findings.^17,18

It is of interest to note that our conclusion on the potential superiority of TCF over TC correlates with the superiority of TCF over TC as reported by Ajani et al¹⁹ in a randomized phase II trial based on the same design. The higher activity of TCF compared with ECF (ORR, 36.6% v 25%, respectively) is also in concordance with the ORR of 37% obtained in 221 TCF-treated patients in a randomized phase III trial, TAX325, comparing TCF with FU-cisplatin.²⁰ The ORR of 25% obtained with ECF is lower than rates previously reported for ECF (42% and 45%); however, responses in those studies were not centrally reviewed, and some were assessed endoscopically, the validity of which remains controversial.^3,21 Additionally, more patients with advanced locoregional disease without distant metastasis were included in the ECF arm of these studies (37% and 45%)^3,21 than in the current trial (17%). Patients with locoregional advanced disease generally respond better to therapy and have a better prognosis.

Like other docetaxel trials in metastatic gastric cancer in which hematotoxicity was the major adverse effect, the TCF regimen was associated with a high incidence of febrile neutropenia, which occurred in 41% of patients compared with only 18% and 21% of patients in the ECF and TC arms, respectively. However, this higher incidence of febrile neutropenia did not translate into a higher mortality rate, with only one toxic fatality recorded in the TC group. After dose reduction of docetaxel to 75 mg/m² (from 85 mg/m²), 11% of TCF treatment cycles were complicated by febrile neutropenia in 35% of patients (compared with 50% of patients before dose reduction). According to the literature, docetaxel 75 mg/m² combined with cisplatin ± FU is well tolerated and is the docetaxel dosage most frequently proposed in gastric cancer treatment.^19,22,23 A high occurrence of febrile neutropenia with docetaxel has also been noted in other tumor types, including adjuvant treatment of breast cancer.²⁴ However, the higher incidence of profound neutropenia and neutropenic fever in the current trial compared with previous trials by the same investigators cannot be explained easily, particularly given that patient selection criteria and population are similar (median age of 59 years in the present trial compared with 58 and 55 years in previous trials; performance status of 0 in 60% of patients compared with 50% previously), with the exception of tumor load (< 50% of patients with > one metastatic site v > 80% previously).^10,11 Because docetaxel in gastric cancer was new at the time, it is likely that clinical follow-up during treatment was particularly rigorous (eg, early antibiotic prophylaxis) in the earlier studies.^10,11

Nonhematologic toxicities were generally moderate and predictable. Grade 3 to 4 diarrhea occurred more frequently with TCF than TC or ECF, possibly because of simultaneous administration of docetaxel and FU. Occurrence of severe neuromotor and neurosensory dysfunctions were similar with docetaxel-based therapy and ECF.

Overall, the QOL scores indicated that all three regimens were well tolerated. The main symptoms (fatigue and appetite loss) were maintained at baseline levels. Although the QOL evaluation was not powered for a formal treatment comparison, there was a suggestion that, over the first 6 months of treatment, ECF patients had a better health status/QOL and less treatment burden than patients receiving docetaxel-based therapy. Furthermore, TCF was associated with additional median weight loss during treatment and a higher frequency of refusal to continue treatment. These observations may indicate that the benefit of antitumoral activity of TCF in the current study was partially offset by its toxicity. The results for patient-estimated changes from baseline to the start of cycle 2 supported the observed relative health status/QOL improvement with ECF therapy. However, the observed change from baseline to the start of cycle 2 did not correspond to the change that patients estimated retrospectively at this time point.¹³ The wording of the change item in the questionnaire was not specifically focused on treatment, which may explain this finding. Also, many patients did not respond to this indicator at baseline.

In conclusion, TCF is more promising than TC and would be the preferred regimen of the two for comparison against ECF if a phase III study is to be conducted. The docetaxel-based regimens were associated with more hematologic toxicity than ECF, but the toxicity was manageable. With many new agents on the horizon, including novel biologic agents (eg, monoclonal antiepidermal growth factor receptor antibodies), we feel that further large-scale evaluation of TCF may not be appropriate in advanced gastric carcinoma. However, in patients requiring a rapid tumor regression especially in a neoadjuvant setting, TCF may be the regimen of choice for the time being.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Stephen Falk, Roche, Pfizer Inc; Robert Glynne-Jones, Sanofi-aventis Stock: N/A Honoraria: Arnaud D. Roth, Sanofi-aventis; Robert Glynne-Jones, Sanofi-aventis; Filippo de Braud, Sanofi-aventis Research Funds: Stephen Falk, Sanofi-aventis Testimony: N/A Other: Robert Glynne-Jones, Sanofi-aventis

	AUTHOR CONTRIBUTIONS

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Conception and design: Arnaud D. Roth, Nicola Fazio, Jürg Bernhard, Rudolf Maibach, Filippo de Braud

Financial support: Nicola Fazio

Provision of study materials or patients: Arnaud D. Roth, Roger Stupp, Stephen Falk, Piercarlo Saletti, Dieter Köberle, Markus M. Borner, Martin Wernli, Martin Leslie, Robert Glynne-Jones, Lukas Widmer, Matthew Seymour, Filippo de Braud

Collection and assembly of data: Arnaud D. Roth, Nicola Fazio, Roger Stupp, Stephen Falk, Piercarlo Saletti, Dieter Köberle, Martin Wernli, Martin Leslie, Filippo de Braud

Data analysis and interpretation: Arnaud D. Roth, Jürg Bernhard, Kaspar Rufibach

Manuscript writing: Arnaud D. Roth, Roger Stupp, Stephen Falk, Jürg Bernhard, Markus M. Borner, Kaspar Rufibach, Rudolf Maibach, Filippo de Braud

Final approval of manuscript: Arnaud D. Roth, Nicola Fazio, Roger Stupp, Stephen Falk, Jürg Bernhard, Piercarlo Saletti, Dieter Köberle, Markus M. Borner, Kaspar Rufibach, Rudolf Maibach, Martin Wernli, Martin Leslie, Robert Glynne-Jones, Lukas Widmer, Matthew Seymour, Filippo de Braud

	ACKNOWLEDGMENTS

 
We are grateful to Sanofi-aventis for the financial support it provided to this study. We thank Brigitte Küenzle, the trial coordinator at the Swiss Group for Clinical Cancer Research Coordinating Center, for accompanying this trial.

	NOTES

 
Supported in part by Sanofi-aventis.

Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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9. Taguchi T: An early phase II clinical study of RP56976 (docetaxel) in patients with cancer of the gastrointestinal tract. Gan To Kagaku Ryoho 21:2431-2437, 1994[Medline]

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13. Bernhard J, Maibach R, Thurlimann B, et al: Patients’ estimation of overall treatment burden: Why not ask the obvious? J Clin Oncol 20:65-72, 2002[Abstract/Free Full Text]

14. Hurny C, Bernhard J, Bacchi M, et al: The Perceived Adjustment to Chronic Illness Scale (PACIS): A global indicator of coping for operable breast cancer patients in clinical trials—Swiss Group for Clinical Cancer Research (SAKK) and the International Breast Cancer Study Group (IBCSG). Support Care Cancer 1:200-208, 1993[CrossRef][Medline]

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18. Ychou M, Pignon JP, Lasser P, et al: Phase III preliminary results of preoperative fluorouracil (F) and cisplatin (P) versus surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC 94012-FFCD 9703 trial. J Clin Oncol 24:185s, 2006 (suppl 18, abstr 4026)

19. Ajani JA, Fodor MB, Tjulandin SA, et al: Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol 23:5660-5667, 2005[Abstract/Free Full Text]

20. 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 24:4991-4997, 2006[Abstract/Free Full Text]

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Submitted June 23, 2006; accepted November 2, 2006.

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