- Email: [email protected]
The treatment of advanced gastric cancer: current strategies and future perspectives
symposium article
Annals of Oncology 19 (Supplement 5): v103–v107, 2008 doi:10.1093/annonc/mdn321
The treatment of advanced gastric cancer: current strategies and future perspectives A. Cervantes, S. Rosello´, D. Roda & E. Rodrı´guez-Braun
introduction The treatment of advanced gastric cancer is essentially palliative. Therapy’s main aim in this common group of patients with unresectable or metastatic disease is to achieve good symptomatic control, to improve quality of life, to avoid tumor progression and to prolong survival. Although gastric cancer has been considered as a chemosensitive tumor for many years, no significant progress in its management has resulted within the last two decades. Most responses to chemotherapy are partial and of short duration. Median survival is 7–9 months and survival at 2 years is exceptionally >10% [1]. Current trials of chemotherapy for advanced disease include patients not only with gastric cancer, but also those suffering from tumors located at the lower third of the esophagus and the gastro-esophageal junction. It is accepted that they may show similar responses to chemotherapy, although the clinical behavior and biology may be different. This review will cover the principles of therapy, underlining the current standard of care. Some future perspectives on new lines of clinical research will also be presented.
prognostic factors in advanced gastric cancer Prognostic factors are important when designing and interpreting therapeutic trials in any human tumor. There are studies on prognostic factors coming from institutional series or derived from analysis of randomized trials. Both sources have limitations and bias. In general, it is accepted that for advanced gastro-esophageal cancer neither primary tumor location nor histological type has any prognostic impact on survival. In a series of 1080 patients treated in three consecutive trials between 1992 and 2001, the probability of responding to chemotherapy was significantly reduced for individuals with a performance status (PS) of 2, with liver or peritoneal metastases and high serum levels of alkaline phosphatase [2]. The same factors also showed a significant effect on survival in a multivariate analysis. In patients presenting none of the previously referred factors median survival was 1 year. If one or two of them were present median survival was 7.4 months, whereas it went down to 4 months if three or four unfavorable factors were detected. In
another series of 1455 patients with advanced disease the importance of poor performance status and elevation of alkaline phosphatase as negative predictors were confirmed [3]. However, multivariate analysis underlines the significance of other negative findings such as the presence of ascites, serum albumin <3.6 g/dl, bone metastases and the absence of primary tumor resection. One-third of the patients analyzed had none or just one of those negative predictors and were considered of better prognosis with a median survival of 12.5 months. Most patients presented two to four unfavorable factors and median survival was reduced to 7 months, whereas <4% had more than four negative predictors and therefore, prognosis was very poor with an estimated median survival of <3 months. The stratification of patients in randomized trials according to wellestablished prognostic factors will avoid bias and may allow a better balance between different study arms.
locally advanced unresectable gastric cancer without distant metastases Preoperative chemotherapy is becoming the standard practice in patients with locally advanced resectable disease. As a consequence preoperative staging is improving. Therefore, the number of patients in whom a laparotomy will detect unresectable primary tumors without metastatic involvement is going to decrease. However, we may still find some patients considered as locally advanced and unresectable based upon clinical or surgical criteria. A series of phase II trials has addressed the value of several combinations of chemotherapeutic agents in patients defined as unresectable after a surgical procedure [4–10]. Most schedules are cisplatin based and showed activity in patients with metastatic disease. Table 1 summarizes the results of seven of those trials. Common findings are a response rate ranging from 48% to 90%, a significant R0 resection rate after three to four courses of therapy going from 45% to 78% and a median survival of 18 months with 20% long-term survivors. Although no data from randomized trials are available, those coming from phase II studies are consistent. Therefore, combination chemotherapy regimens with activity in metastatic disease are also recommended for patients with locally advanced gastric cancer defined as unresectable after a surgical procedure. Managing those patients within a multidisciplinary
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
symposium article
Department of Hematology and Medical Oncology, Hospital Clı´nico Universitario, University of Valencia, Valencia, Spain
symposium article
Annals of Oncology
Table 1. Phase II trials of combination chemotherapy in patients with locally advanced gastric cancer without metastasis and surgically defined as unresectable Author (year)
No. patients
Chemotherapy
No. courses
Response rate (%)
R0 resectability (%)
Median survival (months)
Wilke (1989) Wilke (1990) Kato (1990)
34 10 8
2–5 2–5 1–5
70 (21% CR) 70 88
59 – 62
18 – –
Plukker (1991) Findlay (1994) Schuhmacher (2001) Cascinu (2004)
20 17 41 82
EAP ELF MMC VP16 CDDP-5-FU 5-FU-MTX ECF FAP PELFw
47 80 90 48
70 55 78 45
12 8.4 – 18
4 4 4 4
CR: complete response; CDDP: cisplatin; EAP: etoposide + adriamycin + cisplatin; ECF: epirubicin, 5-FU and cisplatin; ELF: etoposide, leucovorin and 5-FU; MMC: mytomicin C; MTX: methotrexate; PELFw: weekly cisplatin, epirubicin, leucovorin and 5-FU.
Table 2. Randomized trials comparing palliative chemotherapy versus best supportive care Author (year)
Murad (1993) Pyrhonen (1995) Scheithauer (1994) Glimelius (1997)
Schedule
FAMTX versus BSC FEMTX versus BSC ELF versus BSC ELF or LF versus BSC
No. patients
Median survival (months)
P
30/10 17/19 18/19 31/30
9.0/3.0 12.0/3.0 7.5/4.0 8.0/5.0
0.001 0.001 – 0.02
FAMTX: 5-FU, adriamycin, leucovorin and methotrexate; FEMTX: 5-FU, epirubicin, leucovorin and methotrexate; ELF: etoposidoe, leucovorin and 5-FU; LF: leucovorin and 5-FU.
team approach may help in offering them better therapeutic options.
chemotherapy improves survival and symptom control over best supportive care Four randomized trials published in the 1990s compared different chemotherapy schedules with best supportive care (BSC) [11–14]. Although the chemotherapy schedules used may be considered as suboptimal, all trials showed a significant prolongation in survival. Table 2 shows a summary of those studies. When three of those studies [11–13] were included in a meta-analysis [1] with a total number of 184 patients, the overall hazard ratio (HR) of 0.39 [95% confidence interval (CI) 0.28–0.52] in favor of the chemotherapy arms demonstrates a convincing benefit in overall survival over BSC alone, which translates to a benefit in weighted mean average survival of 6 months. An additional study provided important insights about the quality of life of patients in the chemotherapy and BSC arms [14]. The average proportion of the total survival time with a high quality of life was significantly higher in the group of patients randomly assigned to chemotherapy compared with the BSC group (69% versus 47%, respectively; P = 0.05). Those studies confirm that chemotherapy plays an important role as palliative treatment in patients with advanced gastric cancer.
v104 | Cervantes et al.
Chemotherapy is recommended in patients with advanced gastric cancer because it prolongs survival and improves quality of life.
single-agent chemotherapy not recommended The question of treating advanced gastric cancer with singleagent versus combination chemotherapy was addressed by 11 randomized studies [15–25] with a total of 1472 patients pooled in Wagner’s meta-analysis [1]. Eight of these trials were performed during or before the 1990s, when the methodology for designing and analyzing them was not so homogeneous. Most of the studies used 5-fluorouracil (5-FU) in the singleagent arm. The resulting HR of 0.83 (95% CI 0.74–0.93) for survival in favor of combination chemotherapy provides evidence of a statistically significant survival benefit of combination versus single agent chemotherapy. This corresponds to a difference in weighted mean average survival of 1 month. However, because intention-to-treat analysis was not performed in a relevant number of studies, an overestimation of the effect of combination chemotherapy cannot be excluded. Overall treatment-associated toxicities were higher in the combination chemotherapy arms, although this was usually not statistically significant in the individual trials. For those reasons, single-agent therapy is no longer recommended for managing patients with advanced gastric cancer.
optimal combinations for metastatic gastric cancer Although it is frequently stated that there is no international agreement in accepting any particular schedule as standard of care in advanced gastric cancer, there is some evidence coming from a meta-analysis and some randomized trials that should be underlined. It is common that randomized trials in gastric cancer may show significant differences in response rate, but there are only few showing significant differences in overall survival.
Volume 19 | Supplement 5 | July 2008
Annals of Oncology
symposium article
The evidence in this respect comes from the meta-analysis. Three trials addressed the issue of comparing a cisplatin plus 5-FU (CF) doublet versus a triplet in which an anthracycline was added [26–28]. The resulting HR for overall survival of 0.77 (95% CI 0.62–0.91) demonstrates a statistically significant benefit in overall survival in favor of the three-drug combination. Triplets containing anthracyclines, cisplatin and 5-FU were also superior to doublets with 5-FU and anthracyclines (HR of 0.83 and 95% CI 0.76–0.91) [16, 29–33]. The combination of epirubicin, cisplatin and 5-FU (ECF) was studied in at least 4 randomized trials [27, 28, 34–36] giving consistent results. Response rate is 40%, median survival is >9 months and the proportion of patients alive at 1 year is 40%. On the other hand, toxicity is predictable and easy to manage with a very low mortality related to therapy of 0.6%. In the most recently published study of ECF [36], it was demonstrated in a bi-factorial non-inferiority design that oxaliplatin could substitute for cisplatin and capecitabine could also replace 5-FU, turning the treatment into a more convenient and easy to administer schedule. In fact, patients treated with the combination of epirubicin, oxaliplatin and capecitabine (EOX) enjoyed a 48% response rate with a median survival of 11.2 months and 47.9% of them were alive at 1 year. The addition of docetaxel to a doublet including cisplatin and 5-FU (DCF) was also studied in a single international randomized trial. The results of this phase III trial indicated a better response rate, a longer progression-free survival and a significantly prolonged survival for those patients receiving the DCF triplet [37]. Although the quantitative benefit in survival is limited, this trial could also show for the first time in advanced gastric cancer that DCF was able to improve quality of life parameters and induced a more solid clinical benefit over the control arm [38–39]. DCF significantly prolonged time to definitive worsening of Karnofsky PS compared with CF. Those findings indicate that DCF may also be considered as a therapeutic option in patients with advanced gastric cancer, provided they have a PS of 0–1 and can tolerate this combination. Irinotecan also showed activity against advanced gastric cancer. However, no improvement in survival was demonstrated in three reported randomized trials [40–42] or in the pooled analysis. Better tolerability than cisplatin-based combinations is a common observation in those trials.
gastric cancer are elderly with nutritional problems, poor performance status, low albumin and frequent co-morbidities. So, we should take care when we try to apply what we consider improvements coming from trials to populations underrepresented or not represented at all in those studies. Some of them would not tolerate aggressive or toxic therapies.
going from investigational trials to clinical practice
disclosures
Clinical trials are essential for providing solid evidence to make decisions with patients in everyday practice. Unfortunately, clinical research has not been a very active area in gastric cancer treatment and many of the published studies in advanced disease were made in highly selected populations, sometimes underpowered to detect significant differences in critical endpoints as survival and often with a very long period of accrual. For example, recent studies only accrued patients with a PS of 1 or 0, when more than two-thirds of patients presenting in the clinic do so with significant symptoms. Samples accrued in trials are also younger than expected for the overall gastric cancer population. Many patients with advanced
Volume 19 | Supplement 5 | July 2008
future perspectives A real issue is that, although we have more active drugs in gastric cancer (e.g. anthracyclines, taxanes, fluoropyrimidines, platinum derivatives, topoisomerase I inhibitors), compared with advanced colon cancer, our achievement has been so far limited. Median time-to-progression and median survival for advanced gastric cancer patients are half compared with colon cancer patients. Second-line chemotherapy is seldomly given to advanced gastric cancer patients and its use is only based upon phase II reports indicating some activity for non-cross-resistant agents such as irinotecan [43], docetaxel [44] or some experimental agents. However, <15% of patients included in the REAL2 trial got second-line therapy after progression. An approach using sequential doublets, as is done in colon cancer, instead of initiating treatment with aggressive or toxic combinations should be investigated in clinical trials. Despite some advances in the treatment of advanced gastric cancer, these patients still do poorly. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. These therapeutic strategies include epidermal growth factor receptor (EGFR) inhibitors, anti-angiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinase inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of advanced gastric cancer that will probably translate into benefit in the treatment of these common malignancies [45]. But biological agents have only been studied in gastric cancer in very limited series of phase II trials. Some data indicate that trastuzumab [46], bevacizumab [47], cetuximab [48] or panitumumab may require further assessment in this disease. Consequently, patients with advanced gastric cancer should be considered for inclusion in clinical trials of targeted therapies in the search for more effective treatments.
No significant relationships.
references 1. 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 2006; 24: 2903–2909. 2. Chau I, Norman AR, Cunningham D et al. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer—pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004; 22: 2395–2403. 3. Lee J, Lim T, Uhm J et al. Prognostic model to predict survival following first-line chemotherapy in patients with metastatic gastric adenocarcinoma. Ann Oncol 2007; 18: 886–891.
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23. Popov I, Svetislav BJ, Jezdic SD. Bi-weekly 24-hour infusion of high dose 5fluorouracil versus EAP regimen in advanced gastric cancer: A randomised phase II study. Ann Oncol 2002; 13(Suppl 5): 188. 24. Yamamura Y, Miyazaki I, Ogawa M et al. A randomized controlled trial with methotrexate (MTX), 5-fluorouracil (5-FU) and pirarubicin (THP) vs 5-FU alone in advanced or recurrent gastric carcinoma: Tokai Hokuriku THP Study Group. Gan To Kagaku Ryoho 1998; 25: 1543–1548. 25. Levi JA, Fox RM, Tattersall MH et al. Analysis of a prospectively randomized comparison of doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: Implications for future studies. J Clin Oncol 1986; 4: 1348–1355. 26. Kyoto Research Group for Chemotherapy of Gastric Cancer. A randomized, comparative study of combination chemotherapies in advanced gastric cancer: 5-fluorouracil and cisplatin (FP) versus 5-fluorouracil, cisplatin 4-epirubicin (FPEPIR). Anticancer Res 1992; 12: 1983–1988. 27. Kim TW, Choi SJ, Ahn JH et al. A prospective randomized phase III trial of 5fluorouracil and cisplatin (FP) versus epirubicin, cisplatin, and 5-FU (ECF) in the treatment of patients with previously untreated advanced gastric cancer (AGC). Eur J Cancer 2001; 37: S314. 28. 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 2002; 20: 1996–2004. 29. Gastrointestinal Tumor Study Group. Triazinate and platinum efficacy in combination with 5-fluorouracil and doxorubicin: Results of a three arm randomized trial in metastatic gastric cancer. J Natl Cancer Inst 1988; 80: 1011–1015. 30. Coccioni G, Bella M, Zironi S et al. Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: A prospective randomized trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 1994; 12: 2687–2693. 31. Coccioni G, Carlini P, Gamboni A et al. Cisplatin, epirubicin, leucovorin and 5fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Ann Oncol 2003; 14: 1258–1263. 32. Kikuchi K, Wakui A, Shimizu H et al. Randomized controlled study on chemotherapy with 5-FD, ADM plus CDDP in advanced gastric carcinoma. Gan To Kagaku Ryoho 1990; 17: 655–662. 33. Webb A, Cunningham D, Scarffe JH et al. A randomized trial comparing ECF with FAMTX in advanced esophagogastric cancer. J Clin Oncol 1997; 15: 261–267. 34. Roth A, Kolaric K, Zupanc D et al. High doses of 5-fluorouracil and epirubicin with or without cisplatin in advanced gastric cancer: A randomized study. Tumori 1999; 85: 234–238. 35. Webb A, Cunningham D, Scarffe JH et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997; 15: 261–267. 36. Cunningham D, Starling N, Rao S et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008; 358: 36–46. 37. Van Cutsen 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. 38. 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 V325 Study Group. J Clin Oncol 2007; 25: 3205–3209. 39. 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 2007; 25: 3210–3216. 40. Bouche´ O, Raoul JL, Bonnetain F et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: A Fe´de´ration Francophone de Cance´rologie Digestive Group Study—FFCD 9803. J Clin Oncol 2004; 22: 4319–4328.
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41. Moehler M, Eimermacher A, Siebler J et al. Randomized phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) versus 5fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer. Br J Cancer 2005; 92: 2122–2128. 42. Dank M, Zaluski J, Valvere V et al. Randomized phase III trial of irinotecan (CPT 11) 5- FU/folinic acid (FA) vs CDDP–5-FU in first line advanced gastric cancer patients. J Clin Oncol 2005; 23: 308S (Abstr 4003). 43. Assersohn L, Brown G, Cunningham D et al. Phase II study of irinotecan and 5-fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma. Ann Oncol 2004; 15: 64–69. 44. Sulkes A, Smyth J, Sessa C et al. Docetaxel (Taxotere) in advanced gastric cancer: Results of a phase II clinical trial—EORTC Early Clinical Trials Group. Br J Cancer 1994; 70: 380–383.
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symposium article 45. Tabernero J, Macarulla T, Ramos FJ et al. Novel targeted therapies in the treatment of gastric and esophageal cancer. Ann Oncol 2005; 16: 1740–1748. 46. Fujimoto-Ouchi K, Sekiguchi F, Yasuno H et al. Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol 2007; 59: 795–805. 47. Shah MA, Ramanathan RK, Ilson DH et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006; 24: 5201–5206. 48. Pinto C, Di Fabio F, Siena S et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007; 18: 510–517.
doi:10.1093/annonc/mdn321 | v107
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Annals of Oncology 19 (Supplement 5): v103–v107, 2008 doi:10.1093/annonc/mdn321
The treatment of advanced gastric cancer: current strategies and future perspectives A. Cervantes, S. Rosello´, D. Roda & E. Rodrı´guez-Braun
introduction The treatment of advanced gastric cancer is essentially palliative. Therapy’s main aim in this common group of patients with unresectable or metastatic disease is to achieve good symptomatic control, to improve quality of life, to avoid tumor progression and to prolong survival. Although gastric cancer has been considered as a chemosensitive tumor for many years, no significant progress in its management has resulted within the last two decades. Most responses to chemotherapy are partial and of short duration. Median survival is 7–9 months and survival at 2 years is exceptionally >10% [1]. Current trials of chemotherapy for advanced disease include patients not only with gastric cancer, but also those suffering from tumors located at the lower third of the esophagus and the gastro-esophageal junction. It is accepted that they may show similar responses to chemotherapy, although the clinical behavior and biology may be different. This review will cover the principles of therapy, underlining the current standard of care. Some future perspectives on new lines of clinical research will also be presented.
prognostic factors in advanced gastric cancer Prognostic factors are important when designing and interpreting therapeutic trials in any human tumor. There are studies on prognostic factors coming from institutional series or derived from analysis of randomized trials. Both sources have limitations and bias. In general, it is accepted that for advanced gastro-esophageal cancer neither primary tumor location nor histological type has any prognostic impact on survival. In a series of 1080 patients treated in three consecutive trials between 1992 and 2001, the probability of responding to chemotherapy was significantly reduced for individuals with a performance status (PS) of 2, with liver or peritoneal metastases and high serum levels of alkaline phosphatase [2]. The same factors also showed a significant effect on survival in a multivariate analysis. In patients presenting none of the previously referred factors median survival was 1 year. If one or two of them were present median survival was 7.4 months, whereas it went down to 4 months if three or four unfavorable factors were detected. In
another series of 1455 patients with advanced disease the importance of poor performance status and elevation of alkaline phosphatase as negative predictors were confirmed [3]. However, multivariate analysis underlines the significance of other negative findings such as the presence of ascites, serum albumin <3.6 g/dl, bone metastases and the absence of primary tumor resection. One-third of the patients analyzed had none or just one of those negative predictors and were considered of better prognosis with a median survival of 12.5 months. Most patients presented two to four unfavorable factors and median survival was reduced to 7 months, whereas <4% had more than four negative predictors and therefore, prognosis was very poor with an estimated median survival of <3 months. The stratification of patients in randomized trials according to wellestablished prognostic factors will avoid bias and may allow a better balance between different study arms.
locally advanced unresectable gastric cancer without distant metastases Preoperative chemotherapy is becoming the standard practice in patients with locally advanced resectable disease. As a consequence preoperative staging is improving. Therefore, the number of patients in whom a laparotomy will detect unresectable primary tumors without metastatic involvement is going to decrease. However, we may still find some patients considered as locally advanced and unresectable based upon clinical or surgical criteria. A series of phase II trials has addressed the value of several combinations of chemotherapeutic agents in patients defined as unresectable after a surgical procedure [4–10]. Most schedules are cisplatin based and showed activity in patients with metastatic disease. Table 1 summarizes the results of seven of those trials. Common findings are a response rate ranging from 48% to 90%, a significant R0 resection rate after three to four courses of therapy going from 45% to 78% and a median survival of 18 months with 20% long-term survivors. Although no data from randomized trials are available, those coming from phase II studies are consistent. Therefore, combination chemotherapy regimens with activity in metastatic disease are also recommended for patients with locally advanced gastric cancer defined as unresectable after a surgical procedure. Managing those patients within a multidisciplinary
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
symposium article
Department of Hematology and Medical Oncology, Hospital Clı´nico Universitario, University of Valencia, Valencia, Spain
symposium article
Annals of Oncology
Table 1. Phase II trials of combination chemotherapy in patients with locally advanced gastric cancer without metastasis and surgically defined as unresectable Author (year)
No. patients
Chemotherapy
No. courses
Response rate (%)
R0 resectability (%)
Median survival (months)
Wilke (1989) Wilke (1990) Kato (1990)
34 10 8
2–5 2–5 1–5
70 (21% CR) 70 88
59 – 62
18 – –
Plukker (1991) Findlay (1994) Schuhmacher (2001) Cascinu (2004)
20 17 41 82
EAP ELF MMC VP16 CDDP-5-FU 5-FU-MTX ECF FAP PELFw
47 80 90 48
70 55 78 45
12 8.4 – 18
4 4 4 4
CR: complete response; CDDP: cisplatin; EAP: etoposide + adriamycin + cisplatin; ECF: epirubicin, 5-FU and cisplatin; ELF: etoposide, leucovorin and 5-FU; MMC: mytomicin C; MTX: methotrexate; PELFw: weekly cisplatin, epirubicin, leucovorin and 5-FU.
Table 2. Randomized trials comparing palliative chemotherapy versus best supportive care Author (year)
Murad (1993) Pyrhonen (1995) Scheithauer (1994) Glimelius (1997)
Schedule
FAMTX versus BSC FEMTX versus BSC ELF versus BSC ELF or LF versus BSC
No. patients
Median survival (months)
P
30/10 17/19 18/19 31/30
9.0/3.0 12.0/3.0 7.5/4.0 8.0/5.0
0.001 0.001 – 0.02
FAMTX: 5-FU, adriamycin, leucovorin and methotrexate; FEMTX: 5-FU, epirubicin, leucovorin and methotrexate; ELF: etoposidoe, leucovorin and 5-FU; LF: leucovorin and 5-FU.
team approach may help in offering them better therapeutic options.
chemotherapy improves survival and symptom control over best supportive care Four randomized trials published in the 1990s compared different chemotherapy schedules with best supportive care (BSC) [11–14]. Although the chemotherapy schedules used may be considered as suboptimal, all trials showed a significant prolongation in survival. Table 2 shows a summary of those studies. When three of those studies [11–13] were included in a meta-analysis [1] with a total number of 184 patients, the overall hazard ratio (HR) of 0.39 [95% confidence interval (CI) 0.28–0.52] in favor of the chemotherapy arms demonstrates a convincing benefit in overall survival over BSC alone, which translates to a benefit in weighted mean average survival of 6 months. An additional study provided important insights about the quality of life of patients in the chemotherapy and BSC arms [14]. The average proportion of the total survival time with a high quality of life was significantly higher in the group of patients randomly assigned to chemotherapy compared with the BSC group (69% versus 47%, respectively; P = 0.05). Those studies confirm that chemotherapy plays an important role as palliative treatment in patients with advanced gastric cancer.
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Chemotherapy is recommended in patients with advanced gastric cancer because it prolongs survival and improves quality of life.
single-agent chemotherapy not recommended The question of treating advanced gastric cancer with singleagent versus combination chemotherapy was addressed by 11 randomized studies [15–25] with a total of 1472 patients pooled in Wagner’s meta-analysis [1]. Eight of these trials were performed during or before the 1990s, when the methodology for designing and analyzing them was not so homogeneous. Most of the studies used 5-fluorouracil (5-FU) in the singleagent arm. The resulting HR of 0.83 (95% CI 0.74–0.93) for survival in favor of combination chemotherapy provides evidence of a statistically significant survival benefit of combination versus single agent chemotherapy. This corresponds to a difference in weighted mean average survival of 1 month. However, because intention-to-treat analysis was not performed in a relevant number of studies, an overestimation of the effect of combination chemotherapy cannot be excluded. Overall treatment-associated toxicities were higher in the combination chemotherapy arms, although this was usually not statistically significant in the individual trials. For those reasons, single-agent therapy is no longer recommended for managing patients with advanced gastric cancer.
optimal combinations for metastatic gastric cancer Although it is frequently stated that there is no international agreement in accepting any particular schedule as standard of care in advanced gastric cancer, there is some evidence coming from a meta-analysis and some randomized trials that should be underlined. It is common that randomized trials in gastric cancer may show significant differences in response rate, but there are only few showing significant differences in overall survival.
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The evidence in this respect comes from the meta-analysis. Three trials addressed the issue of comparing a cisplatin plus 5-FU (CF) doublet versus a triplet in which an anthracycline was added [26–28]. The resulting HR for overall survival of 0.77 (95% CI 0.62–0.91) demonstrates a statistically significant benefit in overall survival in favor of the three-drug combination. Triplets containing anthracyclines, cisplatin and 5-FU were also superior to doublets with 5-FU and anthracyclines (HR of 0.83 and 95% CI 0.76–0.91) [16, 29–33]. The combination of epirubicin, cisplatin and 5-FU (ECF) was studied in at least 4 randomized trials [27, 28, 34–36] giving consistent results. Response rate is 40%, median survival is >9 months and the proportion of patients alive at 1 year is 40%. On the other hand, toxicity is predictable and easy to manage with a very low mortality related to therapy of 0.6%. In the most recently published study of ECF [36], it was demonstrated in a bi-factorial non-inferiority design that oxaliplatin could substitute for cisplatin and capecitabine could also replace 5-FU, turning the treatment into a more convenient and easy to administer schedule. In fact, patients treated with the combination of epirubicin, oxaliplatin and capecitabine (EOX) enjoyed a 48% response rate with a median survival of 11.2 months and 47.9% of them were alive at 1 year. The addition of docetaxel to a doublet including cisplatin and 5-FU (DCF) was also studied in a single international randomized trial. The results of this phase III trial indicated a better response rate, a longer progression-free survival and a significantly prolonged survival for those patients receiving the DCF triplet [37]. Although the quantitative benefit in survival is limited, this trial could also show for the first time in advanced gastric cancer that DCF was able to improve quality of life parameters and induced a more solid clinical benefit over the control arm [38–39]. DCF significantly prolonged time to definitive worsening of Karnofsky PS compared with CF. Those findings indicate that DCF may also be considered as a therapeutic option in patients with advanced gastric cancer, provided they have a PS of 0–1 and can tolerate this combination. Irinotecan also showed activity against advanced gastric cancer. However, no improvement in survival was demonstrated in three reported randomized trials [40–42] or in the pooled analysis. Better tolerability than cisplatin-based combinations is a common observation in those trials.
gastric cancer are elderly with nutritional problems, poor performance status, low albumin and frequent co-morbidities. So, we should take care when we try to apply what we consider improvements coming from trials to populations underrepresented or not represented at all in those studies. Some of them would not tolerate aggressive or toxic therapies.
going from investigational trials to clinical practice
disclosures
Clinical trials are essential for providing solid evidence to make decisions with patients in everyday practice. Unfortunately, clinical research has not been a very active area in gastric cancer treatment and many of the published studies in advanced disease were made in highly selected populations, sometimes underpowered to detect significant differences in critical endpoints as survival and often with a very long period of accrual. For example, recent studies only accrued patients with a PS of 1 or 0, when more than two-thirds of patients presenting in the clinic do so with significant symptoms. Samples accrued in trials are also younger than expected for the overall gastric cancer population. Many patients with advanced
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future perspectives A real issue is that, although we have more active drugs in gastric cancer (e.g. anthracyclines, taxanes, fluoropyrimidines, platinum derivatives, topoisomerase I inhibitors), compared with advanced colon cancer, our achievement has been so far limited. Median time-to-progression and median survival for advanced gastric cancer patients are half compared with colon cancer patients. Second-line chemotherapy is seldomly given to advanced gastric cancer patients and its use is only based upon phase II reports indicating some activity for non-cross-resistant agents such as irinotecan [43], docetaxel [44] or some experimental agents. However, <15% of patients included in the REAL2 trial got second-line therapy after progression. An approach using sequential doublets, as is done in colon cancer, instead of initiating treatment with aggressive or toxic combinations should be investigated in clinical trials. Despite some advances in the treatment of advanced gastric cancer, these patients still do poorly. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. These therapeutic strategies include epidermal growth factor receptor (EGFR) inhibitors, anti-angiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinase inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of advanced gastric cancer that will probably translate into benefit in the treatment of these common malignancies [45]. But biological agents have only been studied in gastric cancer in very limited series of phase II trials. Some data indicate that trastuzumab [46], bevacizumab [47], cetuximab [48] or panitumumab may require further assessment in this disease. Consequently, patients with advanced gastric cancer should be considered for inclusion in clinical trials of targeted therapies in the search for more effective treatments.
No significant relationships.
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