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Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial

Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a... British Journal of Cancer (1999) 80(1/2), 269–272 © 1999 Cancer Research Campaign Article no. bjoc.1998.0350 Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial 1 1 1 2 1 3 4 5 6 JS Waters , A Norman , D Cunningham , JH Scarffe , A Webb , P Harper , JK Joffe , M Mackean , J Mansi , 2 1 1 1 1 1 M Leahy , A Hill , J Oates , S Rao , M Nicolson and T Hickish Cancer Research Campaign (CRC) Section of Medicine and Gastrointestinal Unit, Royal Marsden Hospital and Institute of Cancer Research, Downs Road, 2 3 Sutton, Surrey SM2 5PT, UK; CRC Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK; Department of Medical Oncology, Guys Hospital, St Thomas Street, London SE1 9RT, UK; Imperial Cancer Research Fund Cancer Medicine Research Unit, St James University Hospital, Beckett Street, Leeds LS9 7TF, UK; CRC Department of Medical Oncology, University of Glasgow, Alexander Stone Building, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Department of Medical Oncology, St Georges Hospital, Blackshaw Road, London SW17 0QT, UK Summary We report the final results of a prospectively randomized study that compared the combination of epirubicin, cisplatin and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin and methotrexate (FAMTX) in previously untreated patients with advanced oesophagogastric cancer. Between 1992 and 1995, 274 patients with adenocarcinoma or undifferentiated carcinoma were randomized from eight oncology centres in the UK and analysed for response and survival. The overall response rate was 46% (95% confidence interval (CI), 37–55%) with ECF, and 21% (95% CI, 13–28%) with FAMTX (P = 0.00003). The median survival was 8.7 months with ECF and 6.1 months with FAMTX (P = 0.0005). The 2-year survival rates were 14% (95% CI, 8–20%) for the ECF arm, and 5% (95% CI, 2–10%) for the FAMTX arm (P = 0.03). Histologically complete surgical resection following chemotherapy was achieved in ten patients in the ECF arm (three pathological complete responses to chemotherapy) and three patients in the FAMTX arm (no pathological complete responses). The ECF regimen resulted in a response and survival advantage compared with FAMTX chemotherapy. The probability of long-term survival following surgical resection of residual disease is increased by this treatment. The high response rates seen with ECF support its use in the neoadjuvant setting. Keywords: cancer; chemotherapy; ECF; FAMTX; gastric; oesophagogastric The value of combination chemotherapy in advanced oesophago- patients with colorectal cancer (Lokich et al, 1989). Following the gastric cancer has been clarified. Three randomized clinical trials demonstration of response rates of 71% with moderate toxicity in a have demonstrated the superiority of chemotherapy over best phase II study (Findlay et al, 1994), we undertook a multicentre supportive care alone (Murad et al, 1993; Pyrhonen et al, 1995; randomized study comparing ECF with FAMTX in advanced Glimelius et al, 1997). However, the optimal regimen has not yet oesophagogastric cancer. The initial results of this trial were been established. The combination of 5-fluorouracil (5-FU), reported in 1996 when recruitment was completed (Webb et al, adriamycin and methotrexate (FAMTX) has been considered 1997). At that stage, an advantage for ECF in response rate and standard therapy, with superior response and survival rates survival was evident. However, median follow-up was only 6.1 compared with previous regimens (Wils et al, 1991; Kelsen et al, months and only 75% of patients had died. We now present a final 1992). A combination of cisplatin, epirubicin, leucovorin and 5-FU survival analysis with all patients followed up for 26.9 months or (PELF) has also demonstrated impressive response rates in a more (median 44 months), and 95% of patients having died. randomized study (Cocconi et al, 1994). The regimen of epirubicin, cisplatin and 5-FU (ECF) was developed at the Royal Marsden METHODS Hospital (RMH) and first reported in 1991 (Cunningham et al, 1991). The three drugs in this regimen were selected on the basis of Our methods have been described previously (Webb et al, 1997). their single agent activity in upper gastrointestinal tract tumours Briefly, patients with inoperable adenocarcinoma or undifferenti- (Beer et al, 1983; Cersosimo and Hong, 1986; Machover et al, ated carcinoma of the oesophagus, oesophagogastric junction, 1986), and on the synergy demonstrated between 5-FU and cisplatin or stomach were randomized to receive ECF or FAMTX in preclinical models (Etienne et al, 1991). The 5-FU is delivered as chemotherapy. ECF chemotherapy was administered through a a protracted infusion as this schedule has produced higher response central venous catheter placed in the subclavian vein. 5-FU was –2 rates with less myelotoxicity compared with bolus administration in given as a continuous intravenous infusion at a dose of 200 mg m –1 –2 day for up to 6 months. Epirubicin (50 mg m ) and cisplatin –2 (60 mg m ) were given every 3 weeks to a maximum of 8 cycles. Received 27 August 1998 –2 FAMTX chemotherapy comprised methotrexate 1500 mg m and Revised 4 November 1998 –2 –2 5-FU 1500 mg m on day 1, and doxorubicin 30 mg m on day Accepted 6 November 1998 15. Cycles were repeated every 28 days to a maximum of 24 Correspondence to: D Cunningham weeks. Patients were followed up with clinical and symptomatic 269 270 JS Waters et al Table 1 Overall objective response rates RESULTS ECF FAMTX Between July 1992 and June 1995, 274 patients (137 in each arm) (n = 121) (n = 116) were randomized from eight oncology centres in the UK. Eighteen Response No. % No. % P patients were ineligible as described in our previous report (Webb CR + PR 56 46 24 21 0.00003 et al, 1997), and were excluded from the analysis. Therefore, 256 CR 10 8 2 2 patients (126 ECF and 130 FAMTX) were assessable on an inten- PR 46 38 22 19 tion-to-treat basis. The patient characteristics were well matched SD 25 21 24 21 between treatment groups (Webb et al, 1997). PD 23 19 43 37 Insufficient treatment Early death 7 17 Response Toxic death 1 2 Toxicity 5 6 Response analysis is now complete and includes 237 evaluable Patient request 4 – patients (121 ECF and 116 FAMTX). A detailed analysis is presented in Table 1. The response rate was 46% (95% confidence CR, complete response; PR, partial response; SD, stable disease; PD, interval (CI), 37–55%) in the ECF arm, and 21% (95% CI, progressive disease. 13–28%) in the FAMTX arm (P = 0.00003). The response rate for locally advanced disease was 58% (95% CI, 43–72%) (eight complete responses and 17 partial responses) for ECF and 20% (95% CI, 9–34%) (two complete responses and seven partial assessment at each visit, and computerized tomography (CT) scan responses) for FAMTX (P = 0.0002). For metastatic disease, the and endoscopy at 12 and 24 weeks from the start of treatment. response rate was 40% (95% CI, 29–52%) for ECF and 21% (95% Responses were classified according to World Health Organization CI, 13–33%) for FAMTX. (WHO) criteria (Miller et al, 1981). In addition, histological confirmation at endoscopy or surgery was required to satisfy the Survival definition of complete remission. Statistical methods used in the design and analysis of this trial have been described previously All eligible patients were included in the survival analysis on an (Webb et al, 1997). Tumour response rates in the two arms were intention-to-treat basis. All surviving patients have now been compared using the c test. Patient survival and failure-free followed up for at least 26.9 months (median 44 months), and 95% survival was examined using the Kaplan–Meier product-limit of patients have died. The median survival time was 8.7 months method, and treatment arms were compared with the log-rank test. with ECF and 6.1 months with FAMTX (P = 0.0005) (Figure 1). Participants gave written informed consent before they entered the The 1- and 2-year survival rates were 37% (95% CI, 28–45%) and study, which was approved by the individual institutes’ Ethics 14% (95% CI, 8–20%) for the ECF arm, and 22% (95% CI, Committee. 15–29%) and 5% (95% CI, 2–10%) for the FAMTX arm. The ECF FAMTX P = 0.0005 Time since r andomization (y ears) Figure 1 Overall survival curve British Journal of Cancer (1999) 80(1/2), 269–272 © Cancer Research Campaign 1999 Epirubicin, cisplatin and fluorouracil in gastric cancer 271 ECF FAMTX P < 0.0001 01 234 5 Time since r andomization (y ears) Figure 2 Failure-free survival curve median failure-free survival time was 7.4 months with ECF and DISCUSSION 3.3 months with FAMTX (P < 0.0001) (Figure 2). We have shown a definite advantage for the ECF regimen over FAMTX in the treatment of advanced oesophagogastric adenocarci- noma. This final analysis confirms and strengthens the conclusions Surgery of our initial analysis of this study (Webb et al, 1997), showing Twenty-five patients have had a surgical procedure following improved response rates and survival for the ECF arm, which are chemotherapy (19 ECF and six FAMTX). Resection was not sustained beyond 2 years. High levels of activity have been demon- possible or the procedure was performed purely for palliation of strated for a number of regimens in phase II studies (Preusser et al, symptoms in seven patients (six ECF and one FAMTX). Five 1989; Murad et al, 1993; Findlay et al, 1994), but randomized patients had attempted resection of their tumour, but histological comparisons with established regimens have often shown little or no examination revealed that excision was incomplete (four ECF and advantage for the new regimen (Kelsen et al, 1992; Wilke et al, one FAMTX). A histologically complete resection was performed 1995). The EORTC study comparing FAMTX with 5-FU, doxo- in ten patients in the ECF arm, three of whom had a pathological rubicin and mitomycin (FAM) (Wils et al, 1991) was the first study complete response to chemotherapy. Four patients treated with demonstrating a survival advantage between chemotherapy regi- FAMTX had a complete resection with no pathological complete mens, and FAMTX has remained the gold standard of therapy. responses. Another recently reported phase II study has investigated a weekly regimen incorporating cisplatin, leucovorin-modulated 5-FU and epirubicin, with granulocyte colony-stimulating factor Long-term survival and glutathione support (Cascinu et al, 1997). A response rate of Twenty-four patients have survived for 2 or more years (range 62% was reported, with a median survival of 11 months. The 24.6–55.1 months) from randomization (17 (13.5%) ECF and response rate of the ECF regimen was 71% in the phase II study seven (5.4%) FAMTX; P = 0.03). Thirteen patients in the ECF arm (Findlay et al, 1994). The lowering of the response rate in this phase and three in the FAMTX arm had locally advanced disease. III randomized trial is likely to be due to elimination of case-selec- Potentially curative surgery was performed in nine of these tion bias, a commonly observed phenomenon. ECF would therefore patients following chemotherapy (seven ECF and two FAMTX), be an appropriate regimen to act as comparator in future trials. and consolidation radiotherapy performed in two (both ECF). A Long-term survival in advanced oesophagogastric cancer is very total of eight patients (five ECF and three FAMTX) have gone on rare. Previous studies have reported 2-year survival rates for the to receive treatment with a variety of palliative chemotherapy regi- FAMTX regimen of 9–10% (Wils et al, 1991; Murad et al, 1993). mens following progressive or recurrent disease, and six patients In our study, ECF produced a 2-year survival rate of 13.5% have received no further active treatment. Thirteen patients remain compared with 5.4% for FAMTX. It is notable that ECF alive (26.9–55.1 months from randomization), of whom eight are chemotherapy resulted in tumour downstaging sufficient to allow free of disease: six patients in the ECF arm and one in the FAMTX complete resection of previously inoperable tumours in ten arm who subsequently had a complete surgical resection, and one patients, three of whom had no residual tumour in the resected patient treated with ECF who had initially been referred for specimen. Six of these patients remain disease-free. In contrast, chemotherapy following an incomplete surgical resection and only four patients treated with FAMTX had complete resections received no additional treatment subsequently. performed, only one of whom is currently disease-free. © Cancer Research Campaign 1999 British Journal of Cancer (1999) 80(1/2), 269–272 272 JS Waters et al advanced gastro-esophageal cancer using epirubicin and cisplatin in The results of surgery alone in oesophagogastric cancer are poor. combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol 5: Five-year survival rates of 21% have been reported following cura- 609–616 tive resection (Allum et al, 1989). The high response rates seen Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Svensson C, with ECF, particularly in patients with locally advanced disease, Enander LK, Linne T, Sellstrom H and Heuman R (1997) Randomized and the extended survival of patients going on to have complete comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8: 163–168 surgical excision of residual disease provide support for the use of Kelsen D, Atiq OT, Saltz L, Niedzwiecki D, Ginn D, Chapman D, Heelan R, ECF in neoadjuvant therapy. Surgeons should be reassured by the Lightdale C, Vinciguerra V and Brennan M (1992) FAMTX versus etoposide, low rates of progressive disease with this regimen. In this trial, only doxorubicin, and cisplatin: a random assignment trial in gastric cancer. J Clin 5% of patients with locally advanced disease progressed while on Oncol 10: 541–548 Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA and Fryer JG (1989) A prospective ECF chemotherapy and are likely to represent a poor prognostic randomized comparison of continuous infusion fluorouracil with a group. Rather than delaying surgery, neoadjuvant ECF may in fact conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic render tumours more easily resectable, allowing more curative Oncology Program Study. J Clin Oncol 7: 425–432 procedures to be undertaken. A number of phase II studies have Machover D, Goldschmidt E, Chollet P, Metzger G, Zittoun J, Marquet J, investigated preoperative chemotherapy with a variety of regimens Vandenbulcke JM, Misset JL, Schwarzenberg L, Fourtillan JB, Gaget H and Mathe G (1986) Treatment of advanced colorectal and gastric adenocarcinomas in oesophagogastric cancer, both in patients with resectable and with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 4: 685–696 non-resectable disease (Wilke et al, 1989; Plukker et al, 1991, Melcher AA, Mort D and Maughan TS (1996) Epirubicin, cisplatin and continuous 1995; Rougier et al, 1994; Melcher et al, 1996). These support infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastro- the principle of neoadjuvant chemotherapy, producing extended oesophageal cancer. Br J Cancer 74: 1651–1654 Miller AB, Hoogstraten B, Staquet M and Winkler A (1981) Reporting results of disease-free and overall survival compared with historical controls. cancer treatment. Cancer 47: 207–214 High rates of complete resection have been reported in patients Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA and Rausch M with initially unresectable locally advanced disease. These series (1993) Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in are difficult to compare because of different criteria for selecting advanced gastric cancer. Cancer 72: 37–41 patients, and the small numbers of patients involved. The MAGIC Plukker JT, Mulder NH, Sleijfer DT, Grond J and Verschueren RCJ (1991) Chemotherapy and surgery for locally advanced cancer of the cardia and trial, which randomizes patients with operable gastric cancer to fundus: phase II study with methotrexate and 5-fluorouracil. Br J Surg 78: receive peri-operative ECF or surgery alone, currently being under- 955–958 taken by the Medical Research Council in conjunction with the Plukker JT, Sleijfer DT, Verschueren RCJ, Van der Graaf WTA and Mulder NH British Gastric Cancer Group, will provide definitive evidence as to (1995) Neo-adjuvant chemotherapy with carboplatin, 4-epiadriamycin and teniposide (CET) in locally advanced cancer of the cardia and lower the efficacy of this approach. oesophagus: a phase II study. Anticancer Res 15: 2357–2362 Preusser P, Wilke H, Achterrath W, Fink U, Lenaz L, Heinicke A, Meyer J, Meyer ACKNOWLEDGEMENTS HJ and Buente H (1989) Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol We thank Michael Crawford for his contribution to this study. 7: 1310–1317 Pyrhonen S, Kuitunen T, Nyandoto P and Kouri M (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive REFERENCES care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71: 587–591 Allum WH, Powell DJ, McConkey CC and Fielding JW (1989) Gastric cancer: a 25- Rougier P, Mahjoubi M, Lasser P, Ducreux M, Oliveira J, Ychou M, Pignon JP, Elias year review. Br J Surg 76: 535–540 D, Bellefqih S, Bognel C, Lusinchi A, Cvitkovic E and Droz JP (1994) Beer M, Cocconi G, Ceci G, Varini M and Cavalli F (1983) A phase II study of Neoadjuvant chemotherapy in locally advanced gastric carcinoma – a phase II cisplatin in advanced gastric cancer. Eur J Cancer Clin Oncol 19: 717–720 trial with combined continuous intravenous 5-fluorouracil and bolus Cascinu S, Labianca R, Alessandroni P, Marcellini M, Silva RR, Pancera G, Testa E, cisplatinum. Eur J Cancer 30A: 1269–1275 Martignoni G, Barni S, Frontini L, Zaniboni A, Luporini G, Cellerino R and Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK, Hughes M, Catalano G (1997) Intensive weekly chemotherapy for advanced gastric cancer Mansi J, Findlay M, Hill A, Oates J, Nicolson M, Hickish T, O’Brien M, using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and Iveson T, Watson M, Underhill C, Wardley A and Meehan M (1997) filgrastim: a report from the Italian Group for the Study of Digestive Tract Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus Cancer. J Clin Oncol 15: 3313–3319 fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric Cersosimo RJ and Hong WK (1986) Epirubicin: a review of the pharmacology, cancer. J Clin Oncol 15: 261–267 clinical activity, and adverse effects of an adriamycin analogue. J Clin Oncol 4: Wilke H, Preusser P, Fink U, Gunzer U, Meyer HJ, Meyer J, Siewert JR, Achterrath 425–439 W, Lenaz L, Knipp H and Schmoll HJ (1989) Preoperative chemotherapy in Cocconi G, Bella M, Zironi S, Algeri R, Di Costanzo F, De Lisi V, Luppi G, locally advanced and nonresectable gastric cancer: a phase II study with Mazzocchi B, Rodino C, Soldani M, Gilli G and Finardi C (1994) Fluorouracil, etoposide, doxorubicin and cisplatin. J Clin Oncol 7: 1318–1326 doxorubicin, and mitomycin combination versus PELF chemotherapy in Wilke H, Wils J, Rougier P, Lacave A, Van Cutsem E, Vanhoeferi U, Sahmoud T, advanced gastric cancer: a prospective randomized trial of the Italian Oncology Curran D and Marinus A (1995) Preliminary analysis of a randomized phase III Group for Clinical Research. J Clin Oncol 12: 2687–2693 trial of FAMTX versus ELF versus cisplatin/FU in advanced gastric cancer. A Cunningham D, Mansi J, Ford HT, Nash AT and Menzies Gow N (1991) Epirubicin, trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group and the Cisplatin and 5-Fluorouracil (ECF) Is Highly Effective In Advanced Gastric AIO (Arbeitsgemeinschaft Internistische Onkologie) (Meeting abstract). Proc Cancer (Meeting Abstract). Proc Annu Meet Am Soc Clin Oncol 10: 136 Annu Meet Am Soc Clin Oncol 14: 206 Etienne MC, Bernard S, Fischel JL, Formento P, Gioanni J, Santini J, Demard F, Wils JA, Klein HO, Wagener DJ, Bleiberg H, Reis H, Korsten F, Conroy T, Fickers Schneider M and Milano G (1991) Dose reduction without loss of efficacy for M, Leyvraz S, Buyse M and Duez N (1991) Sequential high-dose methotrexate 5-flourouracil and cisplatin combined with folinic acid. In vitro study on and fluorouracil combined with doxorubicin – a step ahead in the treatment of human head and neck carcinoma cell lines. Br J Cancer 63: 372–377 advanced gastric cancer: a trial of the European Organization for Research and Findlay M, Cunningham D, Norman A, Mansi J, Nicolson M, Hickish T, Nicolson Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 9: V, Nash A, Sacks N, Ford H, Carter R and Hill A (1994) A phase II study in 827–831 British Journal of Cancer (1999) 80(1/2), 269–272 © Cancer Research Campaign 1999 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial

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Springer Journals
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Copyright © 1999 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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1532-1827
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10.1038/sj.bjc.6690350
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Abstract

British Journal of Cancer (1999) 80(1/2), 269–272 © 1999 Cancer Research Campaign Article no. bjoc.1998.0350 Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial 1 1 1 2 1 3 4 5 6 JS Waters , A Norman , D Cunningham , JH Scarffe , A Webb , P Harper , JK Joffe , M Mackean , J Mansi , 2 1 1 1 1 1 M Leahy , A Hill , J Oates , S Rao , M Nicolson and T Hickish Cancer Research Campaign (CRC) Section of Medicine and Gastrointestinal Unit, Royal Marsden Hospital and Institute of Cancer Research, Downs Road, 2 3 Sutton, Surrey SM2 5PT, UK; CRC Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK; Department of Medical Oncology, Guys Hospital, St Thomas Street, London SE1 9RT, UK; Imperial Cancer Research Fund Cancer Medicine Research Unit, St James University Hospital, Beckett Street, Leeds LS9 7TF, UK; CRC Department of Medical Oncology, University of Glasgow, Alexander Stone Building, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Department of Medical Oncology, St Georges Hospital, Blackshaw Road, London SW17 0QT, UK Summary We report the final results of a prospectively randomized study that compared the combination of epirubicin, cisplatin and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin and methotrexate (FAMTX) in previously untreated patients with advanced oesophagogastric cancer. Between 1992 and 1995, 274 patients with adenocarcinoma or undifferentiated carcinoma were randomized from eight oncology centres in the UK and analysed for response and survival. The overall response rate was 46% (95% confidence interval (CI), 37–55%) with ECF, and 21% (95% CI, 13–28%) with FAMTX (P = 0.00003). The median survival was 8.7 months with ECF and 6.1 months with FAMTX (P = 0.0005). The 2-year survival rates were 14% (95% CI, 8–20%) for the ECF arm, and 5% (95% CI, 2–10%) for the FAMTX arm (P = 0.03). Histologically complete surgical resection following chemotherapy was achieved in ten patients in the ECF arm (three pathological complete responses to chemotherapy) and three patients in the FAMTX arm (no pathological complete responses). The ECF regimen resulted in a response and survival advantage compared with FAMTX chemotherapy. The probability of long-term survival following surgical resection of residual disease is increased by this treatment. The high response rates seen with ECF support its use in the neoadjuvant setting. Keywords: cancer; chemotherapy; ECF; FAMTX; gastric; oesophagogastric The value of combination chemotherapy in advanced oesophago- patients with colorectal cancer (Lokich et al, 1989). Following the gastric cancer has been clarified. Three randomized clinical trials demonstration of response rates of 71% with moderate toxicity in a have demonstrated the superiority of chemotherapy over best phase II study (Findlay et al, 1994), we undertook a multicentre supportive care alone (Murad et al, 1993; Pyrhonen et al, 1995; randomized study comparing ECF with FAMTX in advanced Glimelius et al, 1997). However, the optimal regimen has not yet oesophagogastric cancer. The initial results of this trial were been established. The combination of 5-fluorouracil (5-FU), reported in 1996 when recruitment was completed (Webb et al, adriamycin and methotrexate (FAMTX) has been considered 1997). At that stage, an advantage for ECF in response rate and standard therapy, with superior response and survival rates survival was evident. However, median follow-up was only 6.1 compared with previous regimens (Wils et al, 1991; Kelsen et al, months and only 75% of patients had died. We now present a final 1992). A combination of cisplatin, epirubicin, leucovorin and 5-FU survival analysis with all patients followed up for 26.9 months or (PELF) has also demonstrated impressive response rates in a more (median 44 months), and 95% of patients having died. randomized study (Cocconi et al, 1994). The regimen of epirubicin, cisplatin and 5-FU (ECF) was developed at the Royal Marsden METHODS Hospital (RMH) and first reported in 1991 (Cunningham et al, 1991). The three drugs in this regimen were selected on the basis of Our methods have been described previously (Webb et al, 1997). their single agent activity in upper gastrointestinal tract tumours Briefly, patients with inoperable adenocarcinoma or undifferenti- (Beer et al, 1983; Cersosimo and Hong, 1986; Machover et al, ated carcinoma of the oesophagus, oesophagogastric junction, 1986), and on the synergy demonstrated between 5-FU and cisplatin or stomach were randomized to receive ECF or FAMTX in preclinical models (Etienne et al, 1991). The 5-FU is delivered as chemotherapy. ECF chemotherapy was administered through a a protracted infusion as this schedule has produced higher response central venous catheter placed in the subclavian vein. 5-FU was –2 rates with less myelotoxicity compared with bolus administration in given as a continuous intravenous infusion at a dose of 200 mg m –1 –2 day for up to 6 months. Epirubicin (50 mg m ) and cisplatin –2 (60 mg m ) were given every 3 weeks to a maximum of 8 cycles. Received 27 August 1998 –2 FAMTX chemotherapy comprised methotrexate 1500 mg m and Revised 4 November 1998 –2 –2 5-FU 1500 mg m on day 1, and doxorubicin 30 mg m on day Accepted 6 November 1998 15. Cycles were repeated every 28 days to a maximum of 24 Correspondence to: D Cunningham weeks. Patients were followed up with clinical and symptomatic 269 270 JS Waters et al Table 1 Overall objective response rates RESULTS ECF FAMTX Between July 1992 and June 1995, 274 patients (137 in each arm) (n = 121) (n = 116) were randomized from eight oncology centres in the UK. Eighteen Response No. % No. % P patients were ineligible as described in our previous report (Webb CR + PR 56 46 24 21 0.00003 et al, 1997), and were excluded from the analysis. Therefore, 256 CR 10 8 2 2 patients (126 ECF and 130 FAMTX) were assessable on an inten- PR 46 38 22 19 tion-to-treat basis. The patient characteristics were well matched SD 25 21 24 21 between treatment groups (Webb et al, 1997). PD 23 19 43 37 Insufficient treatment Early death 7 17 Response Toxic death 1 2 Toxicity 5 6 Response analysis is now complete and includes 237 evaluable Patient request 4 – patients (121 ECF and 116 FAMTX). A detailed analysis is presented in Table 1. The response rate was 46% (95% confidence CR, complete response; PR, partial response; SD, stable disease; PD, interval (CI), 37–55%) in the ECF arm, and 21% (95% CI, progressive disease. 13–28%) in the FAMTX arm (P = 0.00003). The response rate for locally advanced disease was 58% (95% CI, 43–72%) (eight complete responses and 17 partial responses) for ECF and 20% (95% CI, 9–34%) (two complete responses and seven partial assessment at each visit, and computerized tomography (CT) scan responses) for FAMTX (P = 0.0002). For metastatic disease, the and endoscopy at 12 and 24 weeks from the start of treatment. response rate was 40% (95% CI, 29–52%) for ECF and 21% (95% Responses were classified according to World Health Organization CI, 13–33%) for FAMTX. (WHO) criteria (Miller et al, 1981). In addition, histological confirmation at endoscopy or surgery was required to satisfy the Survival definition of complete remission. Statistical methods used in the design and analysis of this trial have been described previously All eligible patients were included in the survival analysis on an (Webb et al, 1997). Tumour response rates in the two arms were intention-to-treat basis. All surviving patients have now been compared using the c test. Patient survival and failure-free followed up for at least 26.9 months (median 44 months), and 95% survival was examined using the Kaplan–Meier product-limit of patients have died. The median survival time was 8.7 months method, and treatment arms were compared with the log-rank test. with ECF and 6.1 months with FAMTX (P = 0.0005) (Figure 1). Participants gave written informed consent before they entered the The 1- and 2-year survival rates were 37% (95% CI, 28–45%) and study, which was approved by the individual institutes’ Ethics 14% (95% CI, 8–20%) for the ECF arm, and 22% (95% CI, Committee. 15–29%) and 5% (95% CI, 2–10%) for the FAMTX arm. The ECF FAMTX P = 0.0005 Time since r andomization (y ears) Figure 1 Overall survival curve British Journal of Cancer (1999) 80(1/2), 269–272 © Cancer Research Campaign 1999 Epirubicin, cisplatin and fluorouracil in gastric cancer 271 ECF FAMTX P < 0.0001 01 234 5 Time since r andomization (y ears) Figure 2 Failure-free survival curve median failure-free survival time was 7.4 months with ECF and DISCUSSION 3.3 months with FAMTX (P < 0.0001) (Figure 2). We have shown a definite advantage for the ECF regimen over FAMTX in the treatment of advanced oesophagogastric adenocarci- noma. This final analysis confirms and strengthens the conclusions Surgery of our initial analysis of this study (Webb et al, 1997), showing Twenty-five patients have had a surgical procedure following improved response rates and survival for the ECF arm, which are chemotherapy (19 ECF and six FAMTX). Resection was not sustained beyond 2 years. High levels of activity have been demon- possible or the procedure was performed purely for palliation of strated for a number of regimens in phase II studies (Preusser et al, symptoms in seven patients (six ECF and one FAMTX). Five 1989; Murad et al, 1993; Findlay et al, 1994), but randomized patients had attempted resection of their tumour, but histological comparisons with established regimens have often shown little or no examination revealed that excision was incomplete (four ECF and advantage for the new regimen (Kelsen et al, 1992; Wilke et al, one FAMTX). A histologically complete resection was performed 1995). The EORTC study comparing FAMTX with 5-FU, doxo- in ten patients in the ECF arm, three of whom had a pathological rubicin and mitomycin (FAM) (Wils et al, 1991) was the first study complete response to chemotherapy. Four patients treated with demonstrating a survival advantage between chemotherapy regi- FAMTX had a complete resection with no pathological complete mens, and FAMTX has remained the gold standard of therapy. responses. Another recently reported phase II study has investigated a weekly regimen incorporating cisplatin, leucovorin-modulated 5-FU and epirubicin, with granulocyte colony-stimulating factor Long-term survival and glutathione support (Cascinu et al, 1997). A response rate of Twenty-four patients have survived for 2 or more years (range 62% was reported, with a median survival of 11 months. The 24.6–55.1 months) from randomization (17 (13.5%) ECF and response rate of the ECF regimen was 71% in the phase II study seven (5.4%) FAMTX; P = 0.03). Thirteen patients in the ECF arm (Findlay et al, 1994). The lowering of the response rate in this phase and three in the FAMTX arm had locally advanced disease. III randomized trial is likely to be due to elimination of case-selec- Potentially curative surgery was performed in nine of these tion bias, a commonly observed phenomenon. ECF would therefore patients following chemotherapy (seven ECF and two FAMTX), be an appropriate regimen to act as comparator in future trials. and consolidation radiotherapy performed in two (both ECF). A Long-term survival in advanced oesophagogastric cancer is very total of eight patients (five ECF and three FAMTX) have gone on rare. Previous studies have reported 2-year survival rates for the to receive treatment with a variety of palliative chemotherapy regi- FAMTX regimen of 9–10% (Wils et al, 1991; Murad et al, 1993). mens following progressive or recurrent disease, and six patients In our study, ECF produced a 2-year survival rate of 13.5% have received no further active treatment. Thirteen patients remain compared with 5.4% for FAMTX. It is notable that ECF alive (26.9–55.1 months from randomization), of whom eight are chemotherapy resulted in tumour downstaging sufficient to allow free of disease: six patients in the ECF arm and one in the FAMTX complete resection of previously inoperable tumours in ten arm who subsequently had a complete surgical resection, and one patients, three of whom had no residual tumour in the resected patient treated with ECF who had initially been referred for specimen. Six of these patients remain disease-free. In contrast, chemotherapy following an incomplete surgical resection and only four patients treated with FAMTX had complete resections received no additional treatment subsequently. performed, only one of whom is currently disease-free. © Cancer Research Campaign 1999 British Journal of Cancer (1999) 80(1/2), 269–272 272 JS Waters et al advanced gastro-esophageal cancer using epirubicin and cisplatin in The results of surgery alone in oesophagogastric cancer are poor. combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol 5: Five-year survival rates of 21% have been reported following cura- 609–616 tive resection (Allum et al, 1989). The high response rates seen Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Svensson C, with ECF, particularly in patients with locally advanced disease, Enander LK, Linne T, Sellstrom H and Heuman R (1997) Randomized and the extended survival of patients going on to have complete comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8: 163–168 surgical excision of residual disease provide support for the use of Kelsen D, Atiq OT, Saltz L, Niedzwiecki D, Ginn D, Chapman D, Heelan R, ECF in neoadjuvant therapy. Surgeons should be reassured by the Lightdale C, Vinciguerra V and Brennan M (1992) FAMTX versus etoposide, low rates of progressive disease with this regimen. In this trial, only doxorubicin, and cisplatin: a random assignment trial in gastric cancer. J Clin 5% of patients with locally advanced disease progressed while on Oncol 10: 541–548 Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA and Fryer JG (1989) A prospective ECF chemotherapy and are likely to represent a poor prognostic randomized comparison of continuous infusion fluorouracil with a group. Rather than delaying surgery, neoadjuvant ECF may in fact conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic render tumours more easily resectable, allowing more curative Oncology Program Study. J Clin Oncol 7: 425–432 procedures to be undertaken. A number of phase II studies have Machover D, Goldschmidt E, Chollet P, Metzger G, Zittoun J, Marquet J, investigated preoperative chemotherapy with a variety of regimens Vandenbulcke JM, Misset JL, Schwarzenberg L, Fourtillan JB, Gaget H and Mathe G (1986) Treatment of advanced colorectal and gastric adenocarcinomas in oesophagogastric cancer, both in patients with resectable and with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 4: 685–696 non-resectable disease (Wilke et al, 1989; Plukker et al, 1991, Melcher AA, Mort D and Maughan TS (1996) Epirubicin, cisplatin and continuous 1995; Rougier et al, 1994; Melcher et al, 1996). These support infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastro- the principle of neoadjuvant chemotherapy, producing extended oesophageal cancer. Br J Cancer 74: 1651–1654 Miller AB, Hoogstraten B, Staquet M and Winkler A (1981) Reporting results of disease-free and overall survival compared with historical controls. cancer treatment. Cancer 47: 207–214 High rates of complete resection have been reported in patients Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA and Rausch M with initially unresectable locally advanced disease. These series (1993) Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in are difficult to compare because of different criteria for selecting advanced gastric cancer. Cancer 72: 37–41 patients, and the small numbers of patients involved. The MAGIC Plukker JT, Mulder NH, Sleijfer DT, Grond J and Verschueren RCJ (1991) Chemotherapy and surgery for locally advanced cancer of the cardia and trial, which randomizes patients with operable gastric cancer to fundus: phase II study with methotrexate and 5-fluorouracil. Br J Surg 78: receive peri-operative ECF or surgery alone, currently being under- 955–958 taken by the Medical Research Council in conjunction with the Plukker JT, Sleijfer DT, Verschueren RCJ, Van der Graaf WTA and Mulder NH British Gastric Cancer Group, will provide definitive evidence as to (1995) Neo-adjuvant chemotherapy with carboplatin, 4-epiadriamycin and teniposide (CET) in locally advanced cancer of the cardia and lower the efficacy of this approach. oesophagus: a phase II study. Anticancer Res 15: 2357–2362 Preusser P, Wilke H, Achterrath W, Fink U, Lenaz L, Heinicke A, Meyer J, Meyer ACKNOWLEDGEMENTS HJ and Buente H (1989) Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. 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British Journal of CancerSpringer Journals

Published: Mar 26, 1999

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