Systemic treatment of gastric cancer

Transcription

1 Critical Reviews in Oncology/Hematology 70 (2009) Systemic treatment of gastric cancer Alessandro Morabito a,, Guido Carillio b, Raffaele Longo c a Clinical Trials Unit, National Cancer Institute, Via Mariano Semmola, Naples, Italy b Department of Medical Oncology, Humanitas Centro Catanese di Oncologia, Catania, Italy c Division of Medical Oncology, San Filippo Neri Hospital, Rome, Italy Accepted 13 August 2008 Contents 1. Introduction Postoperative treatments Adjuvant chemotherapy Adjuvant intraperitoneal chemotherapy Adjuvant radiotherapy Adjuvant chemoradiotherapy Preoperative and perioperative treatments Preoperative chemotherapy Perioperative chemotherapy Preoperative chemoradiotherapy Treatment of advanced disease First-line treatments Second-line treatments Target therapy Angiogenesis inhibitors Epidermal growth factor receptor and HER-2 inhibitors Cell cycle inhibitors Matrix metalloproteinase inhibitors Proteasome inhibitors Other agents Open questions and conclusions Conflict of interest statement Reviewers References Biographies Abstract Treatment of gastric cancer is improved over the past years, but unanswered questions remain regarding the efficacy of systemic treatments in adjuvant, neoadjuvant and metastatic setting. It has not been definitively demonstrated the efficacy of adjuvant chemotherapy, that should not be adopted as a standard approach to localized gastric cancer. On the contrary, compelling evidence in support of perioperative chemotherapy with ECF regimen has been recently provided by the MAGIC trial, although many criticisms Corresponding author. Tel.: ; fax: addresses: alessandromorabito1@virgilio.it, alessandro.morabito@uosc.fondazionepascale.it (A. Morabito) /$ see front matter 2008 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) have been moved to this study. For metastatic setting, a recent meta-analysis showed a small, but significant survival benefit for combination vs single agent chemotherapy, and the V-325 trial demonstrated the superiority of a docetaxel containing regimen (DCF) over a doublet (CF). Finally, the results of ongoing clinical trials on a number of new molecular-targeted drugs should confirm their role in gastric cancer Elsevier Ireland Ltd. All rights reserved. Keywords: Gastric cancer; Neoadjuvant therapy; Adjuvant therapy; Metastatic treatment; Target-based agents 1. Introduction Gastric cancer is the fifth most common malignancy and the second leading cause of cancer mortality in the world, with approximately 930,000 new cases and more than 700,000 deaths estimated in 2006 [1]. Surgical resection is the mainstay of curative treatment, but it can be performed in a small subgroup of patients: only 30 50% of patients undergoing surgical exploration can be operated with curative intent, with 5-year survival rates of about 60% and 34% for stage I and stage II disease, respectively [2]. Clinical trials of neoadjuvant and adjuvant therapy have been conducted to improve these results. New cytotoxic agents have been evaluated in large phase III trials in metastatic setting, showing interesting results. In addition, a number of biological agents modulating different signal transduction pathways are in clinical development. The present review has the purpose to critically summarize the best available evidence for the systemic treatment of gastric cancer, focusing on pitfalls and biases that actually exist. 2. Postoperative treatments 2.1. Adjuvant chemotherapy Several chemotherapeutic agents and regimens have been evaluated in adjuvant setting, often borrowed from metastatic setting. Unfortunately, in more than 30 randomized trials of surgery followed by chemotherapy compared with surgery alone, results have been conflicting, most failing to demonstrate a significant benefit for adjuvant chemotherapy [3 6]. In order to increase the power to detect a benefit from this approach, five meta-analyses of published trials have been performed (Table 1) [7 11]. In general, these analyses showed only a modest survival benefit in favour of adjuvant chemotherapy, that translated into an absolute death risk reduction of 4%, indicating that 25 patients would need to receive adjuvant therapy to prevent 1 death [8]. In addition, a separate analysis documented an advantage only for Asian studies [11]. Only one meta-analysis found that trials in which more than two thirds of patients had lymph node-positive disease were more likely to show benefit from chemotherapy [8]. However, conclusive recommendations are difficult, due to heterogeneity of these meta-analyses in terms of methodological approaches (literature-based review vs pooling of individual patient data), assessment of older chemotherapy regimens or different surgical procedures, small number of patients evaluated in each single study, and finally the combined analysis of Asian and Western studies. Moreover, three phase III randomized trials comparing different chemotherapy regimens with surgery alone failed to demonstrate a significant improvement in disease-free survival (DFS) and overall survival (OS) for adjuvant therapy, even with weekly and more aggressive schedules (Table 2) [12 14]. More recently, S1, an orally active combination of tegafur (a prodrug converted by cells to 5-fluorouracil (5-FU)), gimestat (an inhibitor of dihydropyrimidine dehydrogenase, which degrades 5-FU), and oxonic acid (which inhibits the phosphorylation of 5-FU in the gastrointestinal tract, thereby reducing the gastrointestinal toxicity of 5-FU), was evaluated in a Japanese randomized phase III trial in 1059 patients with stage II/III gastric cancer after extended (D2) gastrectomy [15]. The S1 group had a higher OS than the surgery alone group (p = 0.002), with a 3-year OS and relapse-free survival rate of 80.1% vs 70.1%, and 72.2% vs 59.6%, respectively. Based on these data, after a median follow-up of 2 years, the data and safety monitoring committee recommended discontinuation of the trial and publication of the results. However, considering the differences between Asian and Western patients and the different surgical procedures, these results should be interpreted with caution, particularly with regard to implications for clinical practice in a non- Japanese population. In conclusion, adjuvant systemic chemotherapy should not be adopted as a standard approach to localized gastric cancer, but should be evaluated in well-designed randomized clinical trials [16,17] Adjuvant intraperitoneal chemotherapy Taking into account the natural history of gastric cancer and the high rate of peritoneal recurrence, the use of intraperitoneal chemotherapy as a targeted adjuvant treatment after surgery may be considered a rationale prophylactic and/or therapeutic approach. Its principal aim is to maximize the total amount of drug delivered into the peritoneal surface, while minimizing its systemic circulation. Several randomized trials, most of which have included mitomycin C and/or platinum-based regimens, have been conducted to investigate the additional value of this approach. However, most of these trials were of modest size and showed inconclusive results. In addition, many controversies remain unsolved, including the timing of drug delivery, the effi-

3 218 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) Table 1 Meta-analyses of randomized trials of adjuvant chemotherapy in gastric cancer Author, year Studies Patients Odds ratio (OR) for death/hazard ratio (HR) for mortality Comments Hermans et al. [7], (95% CI: ) All trials were evaluated, including radiotherapy studies. Results not statistically significant Earle et al. [8], (95% CI: ) Only adjuvant chemotherapy trials were evaluated. Asian studies were excluded. Absolute reduction in death rate of 4% (> in lymph nodes positive patients) Mari et al. [9], (95% CI: ) Only adjuvant chemotherapy trials were evaluated. 18% reduction in the relative risk of death. No differences with anthracycline-containing regimens Gianni et al. [10], (95% CI: ) Only adjuvant chemotherapy trials were evaluated. Trials with incompletely resected gastric cancer patients were excluded. Asian studies were included. Statistically significant benefit in survival (p < 0.001) Janunger et al. [11], (95% CI: ) Only adjuvant chemotherapy trials were evaluated. Neoadjuvant and intraperitoneal chemotherapy trials were included in descriptive analysis. Separate analysis of Asian (n = 4) and Western (n = 17) trials. Positive results only in Asian Studies (OR = 0.58) cacy of concomitant hyperthermia and the optimal choice of chemotherapeutic agents. As a result, the regimens used for intraperitoneal administration vary among institutions. A recent meta-analysis evaluated the potential role of adjuvant intraperitoneal chemotherapy on OS, incidence of recurrence, morbidity, mortality, and quality of life [18]. Ten published studies and 5 different intraperitoneal treatments were evaluated, including hyperthermic intraoperative intraperitoneal chemotherapy (HIIC), normothermic intraoperative intraperitoneal chemotherapy (NIIC), early postoperative intraperitoneal chemotherapy (EPIC), delayed postoperative intraperitoneal chemotherapy (DPIC), and finally combined forms of intraperitoneal chemotherapy. A significant survival improvement was found in favour of HIIC (HR = 0.60; p = 0.002), and HIIC combined with EPIC (HR = 0.45; p = ). There was no advantage with NIIC (HR = 0.67; p = 0.06), with EPIC (HR = 0.64; p = 0.11) or DPIC (HR = 0.89; p = 0.68). The four studies reporting peritoneal recurrence data, one using HIIC and the other three NIIC, did not show any significant different peritoneal failure, as compared with the respective control arms. Only one study demonstrated a significant reduction of loco-regional recurrence associated with EPIC (p = 0.008). Regarding toxicity, meta-analysis showed a significant increase of intra-abdominal abscess and neutropenia in the intraperitoneal chemotherapy arm with an increased risk of 137% and 333%, respectively, when compared with control arm. Based on these data, the authors concluded that meta-analysis could offer evidence of a general principle, but it did not prove any conclusive results. Although HIIC was found to be associated with an improved OS, the question of its efficacy in preventing locoregional recurrence could not be answered directly from this analysis. It is acknowledged that this may be partly attributed to inadequacy of intensive follow-up and difficulty in accurately detecting peritoneal recurrence by radiologic examinations. Therefore, intraperitoneal chemotherapy remains an experimental approach and it should not be considered outside of clinical trials. Table 2 Post meta-analyses randomized phase III clinical trials of adjuvant chemotherapy in gastric cancer Author, year Regimen Patients 5-years OS (%) 7-years OS (%) p Bouchè et al. [12], FU/cisplatin vs control Cascinu et al. [13], 2007 PELFw NS vs 5-FU/LV De Vita et al. [14], 2007 ELFE NS vs control PELFw: cisplatin, epirubicin, leucovorin, 5-fluorouracil; w: weekly; ELFE: epirubicin, leucovorin, 5-fluorouracil, etoposide; OS: overall survival; DFS: disease-free survival.

4 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) Adjuvant radiotherapy Only one randomized clinical trial assessed the role of adjuvant external beam radiation therapy (EBRT), and it was conducted by the British Stomach Cancer Group [19]. In this trial, 436 patients with radically resected stage II/III disease were randomized to no further therapy, adjuvant radiotherapy, or adjuvant chemotherapy. Five-year survival for patients receiving adjuvant radiotherapy was 12% compared with 20% for those assigned to surgery alone (p > 0.2); nonetheless, locoregional recurrence was significantly lower in the adjuvant radiotherapy arm (10% vs 27%). Consequently, the benefit of adjuvant radiotherapy alone remains unproven. Moreover, further studies with radiation alone are unlikely to be conducted, given the renewed interest in both neoadjuvant chemotherapy and concurrent chemoradiotherapy [6] Adjuvant chemoradiotherapy The use of postoperative chemoradiation has been evaluated by the Intergroup INT-0116 Trial [20]. In this study, 556 patients who had undergone a curative resection for stage Ib IVa gastric or gastroesophageal junction adenocarcinoma were randomized to either no further therapy or postoperative concurrent chemoradiation. Patients assigned to adjuvant treatment received one course of 5-FU 425 mg/m 2 /d and leucovorin 20 mg/m 2 /d on days 1 5, followed by 45 Gy of radiation during 5 weeks with bolus 5-FU 400 mg/m 2 and leucovorin 20 mg/m 2 on each of the first 4 days and the last 3 days of radiotherapy. One month after completion of radiotherapy, 2 additional cycles of the same initial chemotherapy were administered. In the most recent update, after a median follow-up of 6 years, patients treated with postoperative chemoradiotherapy experienced significant improvement in both DSF (30 vs 19 months, p < 0.001) and OS (35 vs 26 months, p = 0.006), after adjustment for extent of invasion through the stomach wall and nodal status. Toxicity was acceptable, and the rate of treatment-related deaths was low (1% overall), although only 65% of the patients in the treatment arm completed all prescribed therapy. Grade 3 toxic effects occurred in 41% and grade 4 in 32% of the patients treated with chemoradiotherapy. Despite the encouraging results, the trial generated several criticisms, the most important being the suboptimal examination of the lymph node status. In particular, 54% of the patients underwent less than a D1 dissection (removal of the stomach, lesser and greater omentum, and associated N1 nodes), and only 10% had a D2 dissection (more extensive gastrectomy and removal of N2 station nodes, with or without splenectomy and distal pancreasectomy). In addition, the benefits of postoperative chemoradiotherapy appeared to be mostly in the reduction of locoregional recurrence, whereas the rate of distant metastases was not significantly different between the 2 groups. As a result, the aim of the ongoing Intergroup study, Cancer and Leukemia Group B (CALGB) 80101, is to use a more active chemotherapy regimen than 5-FU and leucovorin. After a curative resection of gastric or gastroesophageal junction cancer, 536 patients will be randomized to 5-FU and leucovorin or to ECF (epirubicin, cisplatin, and infusional 5-FU) regimen before and after concurrent infusional 5-FU and radiation. Pending the results of this study, postoperative chemoradiation should be deserved to selected patients, particularly to those who have received a suboptimal gastric resection (D0 lymph node dissection) and/or in case of locoregional micro/macroscopic residual tumor (R1/R2 surgery). 3. Preoperative and perioperative treatments 3.1. Preoperative chemotherapy Several phase II studies have demonstrated the feasibility of a variety of preoperative chemotherapy regimens, with tumor downstaging in up to 50% of patients and pathologic complete responses in 10% of cases, without an apparent excess of perioperative morbidity and mortality [6]. Other potential advantages of this strategy are the reduction of occult micrometastases before the surgery, the prognostic information arising from an evaluation of the pathologic tumor response, and the higher tolerance of treatment-naïve patients to chemotherapy. Nonetheless, only few randomized trials showed a statistically significant improvement of DFS and OS with neoadjuvant chemotherapy [6]. Moreover, it should be considered that the number of patients enrolled in each study was small, limiting the statistical power of the analyses, the used chemotherapy regimens contained older drugs, and the surgical procedures were different, in particular regarding the locoregional lymph nodes dissection. Recently, positive results have been reported by a randomized French study (FFCD 9703), that evaluated the impact of 2 3 cycles of neoadjuvant 5-FU as continuous infusion in combination with cisplatin vs surgery alone in 224 patients with resectable adenocarcinoma of stomach and lower esophagus [21]. After a median follow-up of 5.7 years, preoperative chemotherapy improved the rate of radical resection (84% vs 73%), 3- and 5-year DFS (40% and 34% vs 25% and 21%, respectively), and 3- and 5-year OS (48% and 38% vs 35% and 24%, respectively). However, in this study only 25% of patients had a tumor of the stomach and 2 3 cycles of postoperative chemotherapy with the same regimen were recommended in the experimental arm in case of response and/or stable disease and pathologic positive lymph nodes Perioperative chemotherapy The Medical Research Council Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial recently provided compelling evidence in support of perioperative treatment [22]. In this pivotal study, 503 patients with potentially resectable stages II IVa (T1-3N3M0 or T4N1-2M0) gastric (74%), distal esophageal (14.8%), and gastroesophageal

5 220 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) junction adenocarcinoma (11.2%) were randomly assigned to surgery alone or perioperative chemotherapy, consisting of 3 cycles of preoperative ECF regimen followed by 3 additional postoperative cycles of the same schedule. After a median follow-up of 4 years, patients in the experimental arm experienced a statistically significant improvement of OS compared to surgery alone [2- and 5-year survival: 50% and 36% vs 41% and 23%; median OS: 24 vs 20 months, respectively (p < 0.009)], a better progression-free survival (PFS) (p = 0.001), and a lower rate of local (14% vs 21%) and distal recurrences (24% vs 37%, respectively). Moreover, ECF appeared to produce significant tumor downstaging in both tumor (p = 0.002) and nodal (p = 0.01) disease. Treatment was well tolerated, and the incidence of postoperative complications did not differ between the 2 arms (45.7% vs 45.3%). Despite these results, perioperative ECF did not result in a significant improvement in curative resectability (69% vs 66%, respectively) in the intention-to-treat analysis [22]. In addition, several important criticisms have been moved to this trial. First, in the chemotherapy arm, 80% of patients underwent surgical resection, 66% initiated postoperative treatment and only 42% completed the entire treatment. Only 50% of patients who completed preoperative chemotherapy and surgery completed also postoperative treatment, the main reason (70% of the patients) being disease progression or patient choice. Moreover, because of the trial design, it was impossible to evaluate the relative contribution of the preoperative as opposed to the postoperative therapy. Considering that one fourth of patients had esophageal or gastroesophageal junction, the relative efficacy of the treatment for each tumor site remains uncertain. In subset analyses, the survival benefit associated with ECF was significant only in the group of patients with gastroesophageal junction tumors, whereas the differences for distal esophageal and gastric tumors did not achieve statistical significance. Of course, because the trial was not adequately powered to detect treatment differences within these subgroups, definitive conclusions cannot be drawn. Thirty-one percent of patients did not have tumor size documentation before randomization and tumors were locally staged by computed tomography (CT) scan. Finally, data on pattern of treatment failure were not reported. In light of the results of this trial, several new studies have been initiated (Fig. 1). The UK National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group is now conducting the MAGIC-B trial to examine the addition of bevacizumab to perioperative chemotherapy with the combination of epirubicin, cisplatin, and capecitabine (ECX) in 1100 patients with resectable distal esophageal, gastroesophageal junction, and gastric adenocarcinoma staged by endoscopic ultrasound. The Dutch Gastric Cancer Group has proposed the CRITICS trial that will evaluate, in 788 patients with resectable gastric cancer, perioperative ECX vs preoperative ECX followed by surgery and postoperative concurrent chemoradiation with cisplatin and capecitabine. Lastly, in an effort to compare pre- to post-operative chemotherapy, a cooperative Swiss/Italian group conducted the SAKK 43/99 study, in which patients with resectable gastric cancer were randomly assigned to 4 cycles of preoperatively vs postoperatively docetaxel, cisplatin, and 5-FU (DCF). Unfortunately, the trial was prematurely closed because of the poor accrual. Currently, no definitive conclusions can be drawn about the efficacy of this treatment compared with surgery alone Preoperative chemoradiotherapy Preoperative chemoradiotherapy produced a high rate of pathologic complete responses in a phase II study, where induction chemotherapy with cisplatin, 5-FU, and leucovorin was followed by preoperative concurrent chemoradiation using infusional 5-FU [23]. Among 33 patients, 28 underwent surgery after neoadjuvant treatment, with 30% of them experiencing a pathologic complete response and 24% pathologic partial response. Median survival for all 33 patients was 34 months, but those with a pathologic response had a significantly longer survival (64 vs 13 months, respectively; p = 0.03). Similar results were observed in the Radiation Therapy Oncology Group Trial 9904: 49 patients with endoscopic ultrasound-staged T2/3 resectable gastric cancer were treated with induction cisplatin, infusional 5-FU, and leucovorin for 2 cycles, followed by concurrent chemoradiation with infusional 5-FU plus weekly paclitaxel before surgery [24]. Seventy-seven percent of patients underwent a radical resection and 27% demonstrated a pathologic complete response. Despite these encouraging results, randomized phase III trials are needed to definitely establish the benefit of neoadjuvant chemoradiation in the treatment of operable gastric cancer. 4. Treatment of advanced disease 4.1. First-line treatments Considering the high rate of both local and distant recurrence after radical surgery and the number of patients with unresectable disease at diagnosis [25], the identification of active systemic treatments in order to improve the poor prognosis of metastatic gastric cancer patients is a major issue. The most extensively studied single agents for the treatment of advanced gastric cancer are 5-FU, doxorubicin, mitomycin C, and cisplatin [26 31]. Newer cytotoxic drugs, such as taxanes (docetaxel and paclitaxel), oral fluoropyrimidines (capecitabine, UFT, S1), and topoisomerase inhibitors (irinotecan and topotecan), have also been investigated (Table 3) [32 38]. Despite a small accrual and some methodological issues, such as early stopping or confounding cross-over, four trials comparing chemotherapy vs best supportive care (BSC) demonstrated a better OS for patients undergoing chemotherapy (9 11 months vs 3 4 months; overall HR: 0.39) (Table 4)

6 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) Fig. 1. Clinical design of ongoing randomized phase III trials evaluating the efficacy of neoadjuvant chemotherapy in gastric cancer. ECF: epirubicin, cisplatin, 5-fluorouracil; ECX: epirubicin, oxaliplatin, capecitabine; DCF: docetaxel, cisplatin, 5-fluorouracil; Bv: bevacizumab; RT: radiotherapy; LV: leucovorin; GEJ: gastro-esophageal junction; ADC: adenocarcinoma. Table 3 Single agents for the treatment of advanced gastric cancer Agent RR (%) References 5-fluorouracil (5-FU) 20 [26,27] 5-FU/leucovorin 33.3 [28] Doxorubicin 17 [29] Mitomycin C 30 [30] Cisplatin 25 [31] Docetaxel 15.9 [32] Paclitaxel 20 [33] Capecitabine 19.4 [34] UFT 27 [35] S1 49 [36] Irinotecan 23.3 [37] Topotecan 10 [38] [39 42]. Only one study also found an improved quality of life (QoL) in favour of chemotherapy arm [41]. A recent meta-analysis of 11 studies (1472 patients) evaluating the role of chemotherapy combinations compared to single agent showed a small, but significant survival benefit of approximately 1 month (HR = 0.83) for combination vs single agent chemotherapy, although with an increased toxicity [43]. The combination of 5-FU, doxorubicin and mitomycin (FAM) was one of the first explored regimens, with response rate (RR) of more than 40% and moderate bone marrow suppression [44]. Other regimens were evaluated in phase II and III clinical trials, including CF (cisplatin and 5-FU), FAMTX (5-FU, doxorubicin and high-dose methotrexate), EAP (etoposide, doxorubicin and cisplatin), ELF (etoposide, leucovorin and 5-FU), ECF, PELF (cisplatin, epirubicin, leucovorin and 5-FU) [45 52]. However, results of phase III randomized clinical trials comparing the efficacy of different chemotherapy combinations showed no clear superiority for a single regimen over another (Table 5) [49,53 59,66,69,76]. Newer taxanes regimens have been investigated on the basis of encouraging results observed in monotherapy. Paclitaxel-containing regimens yielded an overall response rate (ORR) of 22 51% and median OS of 6 14 months. Myelosuppression was the most frequent adverse event [60,61]. Several phase II studies evaluated both doublet and triplet docetaxel-based regimens in advanced gastric cancer. Responses were in the range of 33 55%, with a median survival time of 9 10 months [62 65]. In the V-325 Trial, Van Cutsem et al. randomized 445 chemotherapy-naïve patients to receive either docetaxel, cisplatin and daily continuous infusion of 5-FU on days 1 5 every 3 weeks (DCF) or cisplatin on day 1 and daily continuous infusion of 5-FU on days 1 5 every 4 weeks (CF) [66]. Median OS (9.2 vs 8.6 months, p = 0.02), time to tumor progression (TTP) (5.6 vs 3.7 months, p < 0.001) and ORR (37% vs 25%, p = 0.01) were significantly superior for DCF over CF combination. How- Table 4 Selected phase III trials of chemotherapy vs best supportive care (BSC) for advanced gastric cancer Author, year Treatment Patients Response rate (%) Median OS (months) Murad et al. [39], 1993 FAMTX vs BSC vs 3(p = 0.001) Pyrhönen et al. [40], 1995 FEMTX vs BSC vs 3.1 (p = ) Glimelius et al. [41], 1997 ELF/FLv vs BSC vs 5(p = 0.003) FAMTX: 5-fluorouracil, doxorubicin, high-dose methotrexate; FEMTX: 5-fluorouracil, epirubicin, high-dose methotrexate; ELF: etoposide, leucovorin, 5- fluorouracil; FLv: 5-fluorouracil, leucovorin; OS: overall survival.

7 222 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) Table 5 Selected randomized phase III studies comparing the efficacy of different chemotherapy combinations in advanced gastric cancer Author, year Regimen Response rate (%) Median OS (months) Wils et al. [59], 1991 FAM vs FAMTX Kelsen et al. [49], 1992 EAP vs FAMTX Kim et al. [58], 1993 FP vs FAM vs FU Webb et al. [56], 1997 FAMTX vs ECF Vanhoefer et al. [53], 2000 FAMTX vs ELF vs FUP Ross et al. [57], 2002 MCF vs ECF Cocconi et al. [52], 2003 FAMTX vs PELF Van Cutsem et al. [66], 2006 DCF vs CF Roth et al. [69], 2007 ECF vs TC vs TCF Cunningham et al. [76], 2008 ECF vs ECX vs EOF vs EOX FAM: 5-fluorouracil, doxorubicin, mitomycin; FAMTX: 5-fluorouracil, doxorubicin, high-dose methotrexate; EAP: etoposide, doxorubicin, cisplatin; FP: 5- fluorouracil, cisplatin; FU: 5 fluorouracil; ECF: epirubicin, cisplatin, 5-fluorouracil; ELF: etoposide, leucovorin, 5-fluorouracil; FUP: infusional 5-fluorouracil, cisplatin; PELF: cisplatin, epirubicin, leucovorin, 5-fluorouracil; MCF: mitomycin, cisplatin, 5-fluorouracil; DCF: docetaxel, cisplatin, 5-fluorouracil days 1 5 continuous infusion; CF: cisplatin, 5-fluorouracil days 1 5 continuous infusion; TC: docetaxel, cisplatin; TCF: docetaxel, cisplatin, daily 5-fluorouracil for 14 consecutive days; ECX: epirubicin, cisplatin, capecitabine; EOF: epirubicin, oxaliplatin, 5-fluorouracil; EOX: epirubicin, oxaliplatin, capecitabine; OS: overall survival. ever, a worse toxicity was observed in DCF than CF, with grade 3 4 treatment-related adverse events reported in 69% vs 59% of patients, and complicated neutropenia in 29% vs 12% of patients, respectively. Despite the higher toxicity, the addition of docetaxel to CF improved also clinical benefit and QoL [67,68]. Recently, in a multicenter phase II trial, Roth et al. compared the ECF combination with a docetaxel-based regimen, either docetaxel and cisplatin (TC) or docetaxel, cisplatin and 5-FU daily infusion for 14 consecutive days (TCF) [69]. Among 119 evaluable patients, ORR was 25% for ECF, 18.5% for TC, and 36.6% for TCF. Median OS was 8.3, 11.0, and 10.4 months, respectively. Even though TCF was more active than ECF regimen, it caused a considerably higher rate of complicated neutropenia (ECF 34%, TC 49%, TCF 57%), suggesting the need for proper patient selection and management. QoL substantially improved with ECF and remained similar to baseline with both docetaxel regimens. The combination of irinotecan and cisplatin produced ORR between 41% and 58%, with a median OS of about 9 months [70 72]. An ORR of 40% and a median OS of 11.3 months were seen with the combination of irinotecan, 5-FU and leucovorin [73]. Pozzo et al. evaluated the combinations of irinotecan, 5-FU and leucovorin and of irinotecan and cisplatin in a phase II trial including 115 metastatic patients [74]. The ORR and median OS in the two arms were 44.4% vs 32.1%, and 10.7 vs 6.9 months, respectively. In both arms, grade 3 4 neutropenia was very worrying (27% vs 65.7%). Grade 3 4 diarrhea occurred in approximately 23% of patients. Oxaliplatin was evaluated in combination with 5-FU and folinic acid (FOLFOX) in 49 patients with locally advanced or metastatic gastric cancer and showed an ORR of 44.9% and a median OS of 8.6 months. Grade 3 4 neutropenia, thrombocytopenia, and anemia occurred in 38%, 4%, and 11% of patients, respectively. Grade 3 peripheral neuropathy occurred in 21% of patients [75]. Recently, the REAL-2 trial randomly assigned 1002 patients to receive triplet therapy with epirubicin and cisplatin plus either 5-FU (ECF) or capecitabine (ECX), or triplet therapy with epirubicin and oxaliplatin plus either 5- FU (EOF) or capecitabine (EOX) [76]. Median OS and 1-year survival rate in the ECF, ECX, EOF, and EOX groups were 9.9, 9.9, 9.3, and 11.2 months, and 37.7%, 40.8%, 40.4%, and 46.8%, respectively. PFS and RRs did not differ significantly among these regimens. Toxic effects of capecitabine and 5-FU were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism, but with slightly higher incidence of grade 3 4 diarrhea and neuropathy. In conclusion, available data suggest that DCF

8 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) Table 6 Published phase II studies of second-line chemotherapy Author Patients Regimen RR/SD (%) TTP (months) Median OS (months) Lee et al. [77], DTX 16.3/ Barone et al. [78], DTX/L-OHP 10.5/ Rosati et al. [79], DTX/Xelox 29/ Nguyen et al. [80], DTX/EPI 15.5/ Polyzos et al. [81], DTX/CDDP 16/ Kunisaki et al. [82], DTX/CDDP 26.7/ Park et al. [65], DTX/CDDP 17.1/ Kodera et al. [84], PTX weekly 16/ Hironaka et al. [85], PTX weekly 24/ 151 days Arai et al. [86], PTX weekly/doxifluridine 28/ 175 days Lee et al. [87], PTX/CDDP 25/ Shin et al. [88], PTX/CDDP 26.5/ Chun et al. [89], CPT-11 weekly 20/ Ueda et al. [90], CPT-11/CDDP 28/ 104 days 283 days Baek et al. [91], CPT-11/CDDP 15.6/ 113 days 184 days Giuliani et al. [92], CPT-11/MMC 32/ 4 8 Park et al. [93], CPT-11/CDDP 25/ Kim et al. [94], FOLFIRIm 21/ Assersohn et al. [95], FOLFIRI 29/ CPT-11: irinotecan; PTX: paclitaxel; DTX: docetaxel; CDDP: cisplatin; EPI: epirubicin; L-OHP: oxaliplatin; Xelox: capecitabine; RR: response rate; SD: stable disease; TTP: time to tumor progression; OS: overall survival. regimen should be considered as the reference schedule for patients with untreated advanced gastric carcinoma and a good performance status Second-line treatments The role of second-line chemotherapy in gastric cancer is not established. Small phase II studies have been published, particularly evaluating the impact of taxanes and irinotecan, alone or in combination with other agents (Table 6) [65,77 82,84 95]. In 38 patients progressed after ECF or CF regimen, the combination of docetaxel and oxaliplatin showed only a marginal activity, with an ORR and a disease stabilization of 10.5% and 47.3%, and a median TTP and OS of 4 and 8.1 months, respectively. The treatment was well tolerated, neutropenia being the principal toxicity. Thirteen patients (34.2%) also received a third-line chemotherapy with an irinotecan-containing regimen, and their median OS was higher than that of the other patients (16.3 vs 6.0 months), suggesting a potential role of sequential treatments in gastric cancer [78]. Interesting results were also observed with docetaxel alone and/or in combination with epirubicin, cisplatin or capecitabine [65,77,79 83]. The combination schedules showed only a modest increase in activity in terms of ORR as compared to monotherapy, the same results in terms of TTP (2 5 months) and OS (5 8 months) and a worse tolerability. Several studies investigated the role of weekly paclitaxel, as single agent and/or in combination with other compounds, showing promising results, particularly in terms of tolerability [84 88]. Irinotecan, as single agent or in combination with cisplatin, mitomycin C, and 5-FU/leucovorin (FOLFIRI schedule) documented interesting results in terms of activity and tolerability, similar to those observed with taxanes [89 95]. At this stage, considering all these data, no standard second-line chemotherapy can be offered. Although no randomized-controlled trial suggests a benefit of a secondline chemotherapy compared with supportive care alone, the above small recent phase II studies showed interesting results with taxanes and irinotecan, alone and/or in combination. In addition, retrospective analyses suggest that patients responding to a second-line therapy can survive consistently longer than non-responders patients, with symptomatic benefit being a considerable end-point [96]. Unfortunately, at the present there are no validated prognostic or predictive factors that could lead to a better identification of patient candidates for an active second-line treatment. 5. Target therapy The lack of a significant benefit from chemotherapy for the treatment of advanced gastric cancer has prompted research into evaluation of new biological therapies, modulating different targets of signal transduction pathways, that are thought to be overexpressed in gastric cancer (Fig. 2). A number of molecular-targeted drugs are in clinical development, inhibiting angiogenesis, epidermal growth factor receptor, cell cycle, matrix metalloproteinase or proteasome (Table 7). The results of phase II/III trials with moleculartargeted agents in gastric cancer are shown in Table Angiogenesis inhibitors Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular

9 224 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) Fig. 2. Tumor microenvironment and target-based agents. endothelial growth factor (VEGF)-A is one of the most critical angiogenesis regulator and it is commonly overexpressed in a variety of human solid tumors, including gastric cancer [97,98]. Its expression has been correlated with tumor stage and progression in patients with gastric cancer [99,100], and the inhibition of its activity by neutralizing antibodies was effective in a gastric cancer xenograft model [101,102]. Several strategies have been developed to target VEGF, including monoclonal antibodies, such as bevacizumab, and small-molecule tyrosine kinase inhibitors (TKIs). The feasibility and efficacy of the bevacizumabcontaining schedules in metastatic patients has been evaluated in phase II studies. The combination of bevacizumab at 15 mg/kg every 14 days, irinotecan and cisplatin, was active in untreated metastatic patients [103]. Median TTP was 8.3 months and the ORR was 65% in 34 patients with measurable disease. The toxicity profile was acceptable: gastrointestinal bleeding was not significant, while grade 3 4 thromboembolic events and perforation occurred in 25% and 6% of patients, respectively. In patients with cisplatin and irinotecan refractory gastric cancer, the combination of bevacizumab (5 mg/kg every 14 days) and weekly docetaxel showed a 27% of RR [104]. Most common grade 3 4 adverse events were anemia, fatigue, neutropenia; however, rare but severe episodes of gastrointestinal bleeding and arterial thromboembolism occurred. A small phase II study evaluated the activity of the combination of bevacizumab (7.5 mg/kg every 14 days), capecitabine and mitomycin-c in patients with heavily pre-treated advanced

10 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) Table 7 Molecular-targeted agents in clinical development in gastric cancer Target Agent Description Status Angiogenesis Bevacizumab Humanized monoclonal antibody anti-vegf Phase III Sunitinib Small molecule targeting VEGFRs, PDGFR-, and c-kit Phase I II Sorafenib Small molecule targeting RAF, VEGFRs, PDGFR- Phase I II EGFR/HER-2 Cetuximab Chimeric, human-murine immunoglobulin anti-egfr Phase III Matuzumab Humanized monoclonal antibody anti-egfr Phase I Panitumumab Fully human monoclonal antibody anti-egfr Phase II Gefitinib Tyrosine kinase inhibitor of EGFR Phase II Erlotinib Tyrosine kinase inhibitor of EGFR Phase II Trastuzumab Monoclonal antibody anti-her-2 Phase III Lapatinib Small-molecule dual inhibitor of EGFR and HER-2 Phase III Cell cycle Flavopiridol Pan cyclin-dependent kinases inhibitor Phase I II Matrix metalloproteinase Marimastat Matrix metalloproteinases inhibitor Phase III Proteasome Bortezomib Small molecule proteasome inhibitor Phase II Gastrin 17 G17DT Immunogen Phase II EGFR: epidermal growth factor receptor; VEGF: vascular endothelial growth factor; PDGFR: platelet-derived growth factor receptor. colorectal and gastric cancer [105]. One long lasting objective response was reported in four patients with metastatic gastric cancer; thrombocytopenia and bleeding were the most common toxicities of this regimen. The role of bevacizumab in combination with chemotherapy (capecitabine and cisplatin) as first-line treatment will be definitively evaluated by a double-blind, randomized, phase III study (AVAGAST trial). The primary end-point of the study is OS and the estimated enrolment is of 760 patients. Finally a randomized controlled phase III study will assess the safety and efficacy of perioperative ECX +/ bevacizumab in 1100 patients with previously untreated, resectable gastric or gastroesophageal junction cancer (MAGIC-B Study). A different strategy of targeting the VEGF pathway is represented by the VEGF receptors TKIs [106]. In mice bearing TMK-1 human gastric tumors, SU6668 has been shown to suppress peritoneal dissemination [107]. In another TMK-1 xenograft model, vandetanib increased tumor apoptosis and reduced tumor cell proliferation and microvessel density [108]. A phase II trial evaluated the activity of sunitinib, a multitargeted TKI, as single agent at standard doses in patients with previously treated metastatic gastric cancer [109]. Preliminary results showed a tumor control rate of 40% with a good tolerability: the most commonly reported toxic events were grade 1 2 stomatitis, skin discoloration, fatigue, anorexia, diarrhea, and hand-foot syndrome (HFS). Further phase I trials of sunitinib in combination with several chemotherapeutic regimens are currently ongoing. An Asian phase I II study is currently exploring the feasibility of first-line therapy with sorafenib, another multitargeted TKI, in combination with capecitabine and cisplatin in advanced gastric cancer patients. Moreover, a phase I study is evaluating the safety with biologic and proteomic analysis of sorafenib and bevacizumab in refractory solid tumors Epidermal growth factor receptor and HER-2 inhibitors Epidermal growth factor receptor (EGFR) signaling is involved in promoting the growth and survival of various types of solid tumors and it is an attractive target for novel biological anticancer agents [110]. Several strategies have been developed to target EGFR, including monoclonal antibodies and small-molecule TKIs. Three anti-egfr antibodies are in clinical development in gastric cancer, cetuximab, matuzumab, and panitumumab. Cetuximab is a chimeric, human murine immunoglobulin (IgG1) anti-egfr that binds competitively to the EGFR and inhibits cell proliferation, angiogenesis, invasiveness and metastasis [111]. Cetuximab has been evaluated in patients with advanced gastric cancer in combination with different chemotherapeutic agents (fluorouracil, oxaliplatin, irinotecan, carboplatin, taxanes) and with radiotherapy, as front-line or salvage therapy. Two phase II studies showed the feasibility and activity of the combination of cetuximab and chemotherapy as first-line treatment. In the first study, cetuximab at standard doses was combined with FOLFIRI regimen for a maximum of 24 weeks; then cetuximab alone was allowed in patients with a clinical benefit. The ORR was 44.1% and the median TTP was 8 months [112]. The higher toxicity appeared to be limited to neutropenia (42.1%), while grade 3 4 acne-like rash was observed in 21.1% of patients. Similar results were observed with the combination of cetuximab with FUFOX regimen [113]. The ORR was 65.2% and the activity was independent of the EGFR tumor expression. In heavily pre-treated patients, the combination of cetuximab and irinotecan was well tolerated and quite active, with 54% of tumor control rate, observed also in irinotecan pre-treated patients [114]. Further phase II trials of first-line therapy with cetuximab in combination with capecitabine and cisplatin or docetaxel and oxaliplatin are ongoing. Moreover, a phase II study

11 Table 8 Results of phase II and III clinical trials with molecular-targeted agents in gastric cancer Author, year Study phase Pts (no) Line of treatment Schedule OS (months) TTP (months) RR (%) Toxicity Shah [103], 2006 II 47 First Bevacizumab + irinotecan + cisplatin Hypertension, gastric perforation, thromboembolic events Enzinger [104], 2006 II 20 Second Bevacizumab + weekly docetaxel n.a. n.a. 27 Anemia, fatigue, neutropenia, bleeding, thromboembolism Peinert [105], 2006 II 19 (4 GC) Third Bevacizumab + capecitabine + mitomycin Thrombocytopenia, bleeding Bang [109], 2007 II 42 Second Sunitinib as single agent Stomatitis, skin discoloration, fatigue, anorexia, diarrhea, hand-foot syndrome Pinto [112], 2007 II 38 First Cetuximab + FOLFIRI Neutropenia, acne-like rash, diarrhea Lordick [113], 2007 II 52 First Cetuximab + FUFOX Diarrhea, fatigue, skin rash Stein [114], 2007 II 13 Second-fifth Cetuximab + irinotecan Neutropenia, diarrhea Doi [118], 2003 II 75 After first Gefitinib (250 or 500 mg) n.a. n.a. 1.3 Diarrhea, skin rash, anorexia Dragovich [120], 2006 II 44 (GEJ) First Erlotinib Skin rash, fatigue, II 26 (GC) AST/ALT elevation Cortes-Funes [125], 2007 II 21 First Trastuzumab + cisplatin n.a. n.a. 35 Asthenia, vomiting, diarrhea Iqbal [128], 2007 II 47 First Lapatinib CNS ischemia, cardiac ischemia, fatigue, vomiting Schwartz [132], 2001 II 16 First Flavopiridol n.a. n.a. 0 Fatigue, diarrhea, thrombosis Bramhall [141], 2002 III 369 Maintenance Marimastat vs placebo 5.2 vs vs 2.7 a n.a. Musculoskeletal pain and inflammation Ocean [143], 2007 II 12 Second Bortezomib Grade 4 cardiac arrest, stomach perforation, leukopenia II 44 First Bortezomib + irinotecan Vomiting, diarrhea, dehydration, febrile neutropenia, anemia and thrombocytopenia Michaeli [145], 2004 II 102 First G17DT + cisplatin + 5- fluorouracil 8.7 n.a. 50 Grade 3 injection site reactions OS: overall survival; TTP: time to progression; RR: response rate; GC: gastric cancer; GEJ: gastro-esophageal junction. a Statistically significant. 226 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009)

12 A. Morabito et al. / Critical Reviews in Oncology/Hematology 70 (2009) is evaluating the pathologic complete response rate of the combination of cetuximab, paclitaxel, carboplatin and radiotherapy in patients with resectable esophageal and gastric cancer. Finally, a pivotal phase III study, EXPAND (Erbitux in combination with Xeloda and cisplatin in advanced esophago-gastric cancer), is assessing the clinical benefit of cetuximab in combination with cisplatin and capecitabine as a first-line treatment for patients with advanced/metastatic gastric adenocarcinoma including gastroesophageal junction adenocarcinoma. The primary end-point is PFS. Preliminary results of two phase I studies indicate that the combination of weekly matuzumab, a humanized monoclonal anti-egfr IgG1 antibody, and chemotherapy (epirubicin, cisplatin and capecitabine or cisplatin, 5-FU and leucovorin) is well tolerated in the first-line treatment of advanced gastric carcinoma [115,116]. Panitumumab is a recombinant, human IgG2 monoclonal antibody with high affinity for the EGFR. A phase I-II study of perioperative panitumumab in combination with epirubicin, oxaliplatin and capecitabine is currently ongoing in patients with resectable gastroesophageal adenocarcinoma in US, while the German AIO is performing a randomized phase II clinical trial of preoperative chemotherapy with epirubicin, cisplatin and capecitabine in combination with panitumumab in stage II and III gastric cancer [117]. Among EGFR TKIs, both gefitinib and erlotinib were evaluated as single agents in patients with advanced gastric cancer with disappointing results. A modest activity was observed with gefitinib at daily 250 mg or 500 mg in heavily pre-treated patients, with only a disease control of 18% [118]. A possible explanation was that the disease was too advanced for this biological activity to translate into clinical benefit. A pharmacodynamic analysis, performed on 116 available tumor samples from 70 patients of this study, demonstrated that gefitinib reached the tumors at concentrations sufficient to inhibit EGFR activation, but intratumoral phosphorylation of MAPK and Akt was not significantly inhibited by the drug [119]. Erlotinib was evaluated as first-line therapy in a phase II study including patients with advanced gastric cancer and gastroesophageal junction carcinoma [120]. No objective responses were observed in the group of patients with gastric cancer, who presented a median survival of 3.5 months. The molecular correlates were not predictive of the patient therapeutic response. A phase II study is currently evaluating the activity of the combination of erlotinib and bevacizumab in patients with advanced upper gastrointestinal carcinomas, refractory or intolerant to standard systemic therapy. Studies of HER-2 positivity rates in gastric cancer using immunohistochemistry (IHC) have shown a mean value of 18%, while according to a recent study using fluorescence in situ hybridization (FISH) the overexpression of HER- 2 protein was well correlated with gene amplification and both were detected in approximately 7% of gastric cancer cases, without a clear relationship with histological subtypes [121,122]. Trastuzumab, an anti-her-2 monoclonal antibody, exhibited activity in human gastric cells and in tumor xenografts overexpressing HER-2 [123]. The concurrent use of trastuzumab may enhance the cytotoxic effects of chemotherapy in patients with HER-2 positive gastric cancer [124]. Preliminary results of a phase II study showed that trastuzumab combined with cisplatin had a promising activity, with a 35% RR and a 53% control disease rate, in chemo-naïve patients with HER-2 positive advanced gastric cancer [125]. An international randomized phase III study is investigating the role of trastuzumab in combination with chemotherapy as first-line therapy for HER-2 positive adenocarcinoma of the stomach or the gastroesophageal junction (BO18255 Trial). Lapatinib is an oral, dual inhibitor of EGFR and HER-2 [126]. Despite the interesting results showed in HER-2 positive breast cancer [127], lapatinib, as single agent, did not meet the primary end-point in terms of objective responses in first-line therapy of advanced gastric cancer [128]. Molecular correlates of this study suggested that intratumoral gene expression levels of HER-2 and IL-8 and polymorphism in IL-8 were potential molecular predictors for survival. Moreover, polymorphisms in IL-8 and VEGF genes may be potential markers in predicting response in this population [129]. A phase II study will determine if changes in expression of markers involved in the 5-FU pathways are associated with response to treatment with lapatinib and capecitabine in first-line treatment independently of tumor HER-2 status, while a phase III study will evaluate the role of lapatinib in addition to weekly paclitaxel in the second-line treatment of HER-2 amplified advanced gastric cancer Cell cycle inhibitors Cyclin-dependent kinases (CDKs) are required for transit of the cell between the different phases of the cell cycle and can be targeted with small molecules. Flavopiridol is a direct pan CDK inhibitor at nanomolar concentrations, inducing a block in cell cycle progression at the G1 S and G2 M interfaces [130]. In a phase I study, the maximum tolerated dose of flavopiridol was determined to be 40 mg/m 2 /24 h with a 72-h infusion schedule and a complete response was observed in one patient with advanced gastric cancer [131]. However, a phase II study with the same schedule of single agent flavopiridol as first-line therapy of patients with advanced gastric cancer failed to demonstrate any objective response, showing also an unexpected higher incidence of vascular thrombosis, fatigue and diarrhea [132]. Flavopiridol has been also evaluated in combination with chemotherapy in patients with refractory gastric cancer: encouraging results were reported in phase I studies with the combination of flavopiridol, irinotecan and cisplatin, while no objective responses were observed with flavopiridol and taxanes [ ].