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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3188-3190 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.2210
Docetaxel, Cisplatin, and Fluorouracil in Gastric Cancer: Does the Punishment Fit the Crime?Memorial Sloan-Kettering Cancer Center, New York, NY As medical oncologists, we face making decisions every day about the choice of palliative chemotherapy for our patients with advanced malignancies. We are fortunate in esophagogastric cancer to have an increasing armamentarium of chemotherapy agents, including fluoropyrimidines, platinates, taxanes, anthracyclines, and topoisomerase I inhibitors. Targeted therapies affecting the vascular endothelial and the epidermal growth factor receptor pathways are now being screened in phase II and III trials. Despite a myriad of two- and three-drug chemotherapy regimens in the oncology literature, there is no consensus about the optimal chemotherapy for advanced gastric cancer. In deciding which therapy to administer, we must carefully weigh cost, toxicity, and complexity of administration of therapy with the relative efficacy, quality of life (QOL), and tolerance in patients. This includes a careful assessment of the individual patient's performance status, burden of comorbid conditions, and age. When addressing these questions, I take inspiration from The Mikado by Gilbert and Sullivan, whose main character is given the task of doling out the appropriate punishment for particular crimes, including either beheading or boiling in oil for the crime of flirtation. Fortunately for the protagonists and the audience, these punishments are never meted out during the course of the opera. With oncologic therapy having the significant potential to expose patients to toxic complications, what magnitude of benefit from treatment justifies what level of toxicity for patients to endure? Modest advances have clearly been made in the development of chemotherapy for advanced gastric cancer. Single agents achieve responses in 10% to 20% of patients with a median survival time of 6 to 7 months, and the index regimen of cisplatin in combination with continuous-infusion fluorouracil (CF) increases response rates to 20% to 30% and median survival time to 7 to 8 months. Phase III trials that add a third agent to CF, including epirubicin plus CF (ECF) and docetaxel plus CF (DCF), report a 10% increase in response rate to 35% to 40% and a 1-month improvement in median survival time to 9 months but at the cost of increasing toxicity. How can we best evaluate and compare two- and three-drug regimens in gastric cancer to select the best therapy? In this issue, Roth et al1 report a randomized phase II trial comparing ECF, DCF, and the two-drug regimen of docetaxel and cisplatin (DC), with the end point of selecting the superior docetaxel regimen for further phase III evaluation. Also in this issue, Ajani et al2,3 present QOL and clinical benefit data from the pivotal V325 trial comparing DCF with CF. The V325 phase III trial of DCF in gastric cancer, which was recently reported by Van Cutsem et al,4 treated 445 patients with metastatic gastric cancer with either standard CF or DCF. This large and well-conducted trial represents a landmark accomplishment in this disease. Although described as a poor prognosis population, patients treated on V325 had a good performance status (99% had a Karnofsky performance status of 80% to 100%) and were relatively young (median age, 55 years). A significant response rate advantage was seen for DCF compared with CF (37% v 25%, respectively), as well as an improved time to tumor progression (5.6 v 3.7 months, respectively). Although only a modest 0.6-month increase in median survival time was observed for DCF, both 1- and 2-year survival rates were improved by 8% to 9%, with one of the highest 2-year survival rates (18%) ever reported for a chemotherapy trial in gastric cancer. However, the modest gains in this trial occurred at the cost of substantial toxicity. Rates of grade 3 to 4 stomatitis ranged from 21% to 27%, diarrhea ranged from 8% to 18%, neutropenia ranged from 57% to 82%, and febrile neutropenia ranged from 27% to 29%. Rates of hospitalization for these daunting toxicities were not reported by the authors, although deaths from therapy occurred in only 3% to 5% of patients treated. Fifty percent of patients receiving DCF were taken off therapy either because of adverse events from treatment or because of patient withdrawal of consent. With the advent of regulatory approval of docetaxel for the treatment of gastric cancer based on the V325 data, should we routinely use DCF as first-line treatment of patients? Will older patients with poorer performance status be able to tolerate the rigors of such therapy, and are the benefits worth the toxicity? Two studies reported by Ajani et al in this issue present QOL2 and clinical benefit data3 for patients treated on the V325 study and place the toxicity data in another context. DCF resulted in a longer time to 5% deterioration in global QOL measures compared with CF (6.5 v 4.2 months, respectively). Looking at individual QOL measures, time to deterioration was also significantly slower for DCF, with the exception of physical functioning. Although QOL assessment favored DCF over CF, neither regimen led to improvement in QOL, and the title of the paper, "Better Quality of Life..." for DCF should be restated as "Better Preservation of Quality of Life..." for DCF. In a second related article, Ajani et al3 evaluated the clinical benefit of DCF compared with CF in V325. The analyses in this study also focused on rate of decline, rather than improvement, in clinical benefit. DCF significantly improved time to worsening of Karnofsky performance score by one level compared with CF. However, other measures, including time to worsening of weight loss and appetite and time to first use of opiates for pain management, were not significantly different for the two treatment arms, although trends favored the DCF arm. The title of this study should also be restated to indicate that DCF preserved clinical benefit, reflected in a single treatment measure—performance status—compared with CF. Neither article indicates an actual improvement in either QOL or clinical benefit. How do these QOL results compare with other phase III trials reported in the Journal of Clinical Oncology? Two trials of ECF in gastric cancer, one comparing ECF with fluorouracil (FU), doxorubicin, and methotrexate (FAMTX)5 and the other comparing ECF with mitomycin plus CF,6 indicated better preservation of QOL scores for ECF compared with either FAMTX or mitomycin plus CF. However, neither of these studies indicated any improvement in QOL scores for ECF. How do DCF and ECF compare in advanced gastric cancer? In this issue, Roth et al1 report a randomized phase II comparison of ECF, DC, and DCF. The DCF regimen consisted of a 21-day continuous-infusion FU schedule (similar to ECF) and a higher dose of docetaxel (85 mg/m2) compared with a shorter 5-day infusion of FU and a lower dose of docetaxel (75 mg/m2) in the DCF regimen reported by Van Cutsem et al.4 The trial treated a mixture of patients with a performance status of 0 or 1, and the majority of patients (> 80%) had distant metastatic disease. Although the phase II design limits a direct comparison of the treatment arms, the three treatment regimens had comparable rates of confirmed response (range, 18% to 37%), time to tumor progression (range, 3.6 to 4.6 months), and median overall survival (range, 8.3 to 10.4 months). Toxicity was substantial in all three arms, with grade 3 or 4 neutropenia observed in 59% of patients treated with ECF and increasing to 76% to 80% of patients treated with either of the docetaxel regimens. The highest rate of febrile neutropenia (41%) was observed in the DCF arm. These results mirror the hematologic toxicity and neutropenic fever reported in other docetaxel combination trials. Grade 3 or 4 GI toxicities were highest in the FU-containing DCF arm (15% diarrhea and 7% stomatitis), with comparable rates of nausea and vomiting (18% to 26%) across the three treatment arms. Although comparisons are again limited by the phase II trial design, QOL analysis using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 indicated improvement in QOL scores for patients receiving ECF and stable QOL scores on both of the docetaxel arms. DCF resulted in detrimental QOL effects of weight loss and decline in role functioning during therapy, which were likely a consequence of the severity of toxicity. The authors declare DCF to be the superior regimen based on a higher response rate compared with DC, although both regimens had similar overall survival. Ajani et al also opted to select DCF over DC for the V325 trial, despite comparable rates of antitumor response rate, time to progression, and overall survival for DC compared with DCF and despite greater rates of GI toxicity for DCF.7 With the exception of a reduced rate of stomatitis, the 21-day schedule of FU for DCF used by Roth et al1 did not offer any toxicity advantage compared with the 5-day schedule used by Van Cutsem et al.4 Authors reporting phase II and III results for DCF describe the toxicities as manageable.1,4,7 The 50% rate of discontinuation of DCF on the V325 trial for either adverse events or patient refusal of further therapy may argue to the contrary. Given the high degree of neutropenia and neutropenic fever with DCF, prophylactic use of growth factors should be considered; lowering the starting doses of both docetaxel (to 60 mg/m2) and cisplatin (to 60 mg/m2) should also be considered. Data for the ECF regimen indicate no compromise of therapy efficacy using this lower and better tolerated dose of cisplatin.5,6 The dose of FU in DCF is also open to question, given the high rates of mucosal toxicity, and either using lower doses (500 to 600 mg/m2) or shortening the infusion to 4 days should be considered. Are there alternatives to DC or DCF? Thuss-Patience et al8 recently reported a phase II comparison of docetaxel combined with continuous-infusion FU (DF) with ECF, using a 21-day infusion schedule of FU, in 90 patients with metastatic gastric cancer. Response rates (36% to 38%), time to progression (5.3 to 5.5 months), and overall survival (9.5 to 9.7 months) were comparable for DF and ECF. The only GI toxicity that exceeded a rate of 10% was stomatitis (13%) for the DF regimen (compared with a rate of 2% with ECF). Although grade 3 or 4 neutropenia was substantial for DF (42%), neutropenic fever was uncommon (4%). The results for DF compare favorably with DC or DCF and suggest that DF is a more tolerable alternative to DC or DCF, with lower rates of neutropenia and neutropenic fever. Although adopted as the control arm for the V325 trial, a 5-day infusion of FU combined with relatively high-dose cisplatin is no longer universally accepted as either a treatment standard or as the basis for the addition of other agents. In a key phase III trial reported by Vanhoefer et al9 comparing conventional CF with bolus FU regimens (FAMTX and etoposide, leucovorin, and FU) in gastric cancer, all of the regimens tested had limited activity (response rates of 9% to 20%) and substantial toxicity. The authors concluded that CF should be neither a therapy standard nor serve as the basis to add other agents. This trial has had significant influence in subsequent European trials, in particular the investigation of alternative schedules of FU in combination with taxanes, irinotecan, and platinum drugs. A recent phase III trial reported by Al-Batran et al10 in 218 patients with advanced gastric cancer used a weekly or biweekly infusion schedule of FU adapted from colorectal cancer combined with either biweekly cisplatin 50 mg/m2 or oxaliplatin 85 mg/m2. In contrast to the toxicity of conventional CF, this trial demonstrated markedly reduced rates of stomatitis (3% to 4%), diarrhea (6% to 7%), nausea (9% to 10%), neutropenia (10% to 15%), and neutropenic fever (3% to 4%). Response rates ranged from 27% to 38%, and time to progression ranged from 3.8 to 5.7 months. These results indicate a toxicity advantage and argue that weekly or biweekly schedules of these agents should be used in the treatment of gastric cancer. Phase I and II trials are now underway evaluating DCF with such modified schedules in gastric cancer. Data from trials of ECF in gastric cancer consistently indicate low rates of GI toxicities for a protracted low-dose infusion of FU. However, the 21-day infusion is cumbersome compared with weekly or biweekly infusion. Oral FU prodrugs, such as capecitabine, substituted for protracted-infusion FU in both the ECF and CF regimens seem to have comparable efficacy, as reported in recent phase III trials,11,12 and will likely be substituted for protracted-infusion FU in future trials. Although the contribution of epirubicin to ECF has never been demonstrated in a phase III trial in gastric cancer, a recently reported meta-analysis did indicate a 2-month improvement in median survival time for the addition of an anthracycline to CF compared with CF alone.13 However, the data for this comparison were largely derived from a subset analysis from a single phase III trial. Epirubicin adds neutropenia, alopecia, and stomatitis to the toxicity of ECF, and oncologists in the United States have been reluctant to adopt ECF in routine practice, in particular given the demise of anthracycline-containing regimens such as FU, doxorubicin, and mitomycin and FAMTX. Is DCF optimal first-line therapy? Sequential use of doublet regimens or a doublet sequenced with single agents may achieve a better therapeutic index than first-line use of three drugs. Potential doublet regimens using FU include combination with a taxane (DF), cisplatin (CF), or irinotecan (IF); phase II (DF)8 and III trials (CF and IF)10,14 support the activity and tolerance of these combinations. The use of weekly or biweekly infusion of FU is preferable given the superior toxicity profile.10,14 The substitution of oral FU prodrugs, such as capecitabine, for infusional FU11,12 or the substitution of oxaliplatin for cisplatin10,12 is also supported by recent phase III data. A phase III trial evaluating the oral FU prodrug S-1 in combination with cisplatin has recently been completed, and results are pending.16 Alternative doublets based on a platinum agent include combination with a taxane (DC), irinotecan, or FU (CF), although only phase II data support the use of either DC1,7 or irinotecan plus cisplatin.15 The two- or three-drug regimens using docetaxel have consistently high rates of neutropenia compared with other two- and three-drug regimens (CF, IF, and ECF), and this will provide an ongoing challenge for their use in clinical practice. Although DCF indeed represents a new palliative option in gastric cancer, for many patients, the use of sequential one- and two-drug therapies may represent the more tolerable alternative. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: David H. Ilson, Pfizer Inc, Sanofi-aventis, Genentech, Bristol-Myers Squibb Co Expert Testimony: None Other Remuneration: None REFERENCES
1. Roth AD, Fazio N, Stupp R, et al: 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. J Clin Oncol 25:3217-3223, 2007 2. Ajani JA, Moiseyenko VM, Tjulandin S, et al: Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: The V-325 Study Group. J Clin Oncol 25:3210-3216, 2007 3. Ajani JA, Moiseyenko VM, Tjulandin S, et al: Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: The V-325 Study Group. J Clin Oncol 25:3205-3209, 2007 4. 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 5. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261-267, 1997 6. Ross P, Nicolson M, Cunningham D, et al: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996-2004, 2002 7. Ajani J, Fodor MB, Tjulandin SA, et al: A multi-institutional phase II randomized trial of docetaxel plus cisplatin (DC) or DC plus 5-fluorouracil (DCF) in patients with untreated, advanced gastric or gastroesophageal adenocarcinoma. J Clin Oncol 23:5660-5667, 2005 8. Thuss-Patience PC, Kretaschmar A, Repp M, et al: Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil for advanced gastric adenocarcinoma: A randomized phase II study. J Clin Oncol 23:494-501, 2005 9. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 18:2648-2657, 2000 10. Al-Batran S, Hartmann J, Probst S, et al: A randomized phase III trial in patients with advanced adenocarcinoma of the stomach receiving first-line chemotherapy with fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP). J Clin Oncol 24:182s, 2006 (suppl 18, abstr 4016) 11. Kang Y, Kang WK, Shin DB, et al: Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): Efficacy and safety results. J Clin Oncol 24:182s, 2006 (suppl 18, abstr 4018) 12. Cunningham D, Rao S, Starling N, et al: Randomized multicenter phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced esophagogastric cancer: The REAL-2 trial. J Clin Oncol 24:182s, 2006 (suppl 18, abstr 4017) 13. Wagner AD, Grothe W, Haerting J, et al: Chemotherapy in advanced gastric cancer: A systematic review and meta-analysis based on aggregate data. J Clin Oncol 24:2903-2909, 2006 14. Dank M, Zaluski J, Barone C, et al: Randomized phase 3 trial of irinotecan + 5FU/folinic acid vs CDDP + 5FU in first line advanced gastric cancer patients. J Clin Oncol 23:308s, 2005 (suppl 16, abstr 4003) 15. Ajani JA, Baker J, Pisters PW, et al: CPT-11 plus cisplatin in patients with advanced gastric or gastroesophageal junction carcinoma: Results of a phase II study. Cancer 94:641-646, 2002[CrossRef][Medline] 16. Ajani JA, Lee FC, Singh DA, et al: Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 24:663-667, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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