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Adjuvant treatment for radically resected gastric cancer patients: the vexata quaestio.

Introduction

Although many advances have been made in the diagnosis and treatment of gastric cancer, the overall outcome for these patients is still disappointing, with a 5-year survival rate of less than 30% in Western countries.

Surgical resection remains the cornerstone of any curative procedure, and radical gastrectomy with extended lymphadenectomy is now recognised as a reasonably safe procedure. However, the prognosis for patients with locally advanced gastric cancer remains poor, even after potentially curative resection, with a high risk of locoregional and/or distant recurrence, which occurs in almost 60% of patients who undergo R0 resection [1-3].

This highlights the fact that surgery alone is unable to eradicate all locoregional disease and emphasises the need for evaluation of complementary strategies to prevent relapse and to improve survival for gastric cancer patients, either pre-, peri- or postoperatively.

Recently, new data focusing on the extent of gastric resection and on the role of additional treatments has become available and gives new hope for an improved outcome for patients with gastric cancer.

Perioperative treatment

The MAGIC trial strongly suggested that the ECF regimen (epirubicin, cisplatin and protracted 5-FU every 3 weeks) given perioperatively (three cycles of preoperative chemotherapy, followed by surgery, followed by three cycles of postoperative chemotherapy) could represent an attractive treatment option for patients with resectable gastric cancer. Patients receiving perioperative chemotherapy had a significantly better overall survival and disease-free survival, with 36% of patients treated perioperatively alive at 5 years, compared to 23% of patients who were treated with surgery only. On the other hand, approximately 40% of the patients enrolled in the experimental arm of the MAGIC trial did not receive the planned adjuvant part of systemic therapy, perhaps due to decreased tolerance to chemotherapy observed after gastrectomy [4].

The value of any medical treatment, administered either pre- or postoperatively, should be considered according to the quality and extent of surgery, which has been shown to significantly influence the outcome of gastric cancer patients [5,6].

The final results of the ACCORD07-FFCD 9703 trial, presented at the ASCO 2007 meeting, confirmed the MAGIC conclusions in 224 patients with adenocarcinoma of the stomach or lower oesophagus: chemotherapy given perioperatively (2-3 cycles of preoperative 5-FU and cisplatin, followed by surgery, followed by 3-4 cycles of the same regimen given postoperatively) improved R0 resection success rates (87% versus 74%) and 5-year disease-free survival and overall survival (34% versus 21% and 38% versus 24% respectively). Even in this trial, as in the MAGIC trial, only 50% of the patients enrolled in the experimental arm received the planned adjuvant part of systemic therapy [7].

It is important to note that in both these trials patients who received perioperative chemotherapy had a benefit in terms of probability of recovery from disease of about 13% over patients who underwent surgery only (Table 1).

Adjuvant treatments

Adjuvant chemotherapy

The role of adjuvant therapy in gastric cancer has been extensively studied during the past three decades, attempting to improve the prognosis of patients with gastric cancer who undergo curative surgery. To date, no definitive conclusions have been drawn from randomised clinical trials of adjuvant chemotherapy, because few studies have shown a significant positive impact on survival compared with surgery alone. However, these studies often randomised a low number of patients and are clearly underpowered. More favourable results were reported in Asian studies compared with Western trials, but differences in tumour location, prevalence of early stages, extent of preoperative staging evaluation and a more extensive lymphadenectomy may also account for these differences [8].

Moreover, the trials predominantly analysed older chemotherapy regimens, such as FAM (5-FU, adriamycin, and mitomycin-C) or FAM-like regimens, designed before the introduction of cisplatin in the treatment of metastatic disease [9, 10].

Meta-analyses

Several meta-analyses of adjuvant chemotherapy have been published since 1993, aiming to better assess any potential benefit of adjuvant therapy that may have been missed in the individual trials [11-17].

The first meta-analysis was conducted by Hermans et al. and analysed 11 randomised trials (including both Western and Asian patients, with a total of 2096 patients) comparing postoperative adjuvant chemotherapy for gastric cancer to surgery alone. The authors found a non-significant trend towards improved survival [odds ratio (OR) 0.88, 95% confidence interval (CI) = 0.78-1.08] [11]. This analysis, however, was criticised for a lack of statistical power and for the studies included. The same data were updated (only in letter form) in 1994 and showed a significant odds ratio (0.82, 95% CI = 0.68-0.97).

More recent meta-analyses have shown marginal, but significant, benefit of postoperative therapy. The meta-analysis by Earle and Maroun was based on 13 trials with 1990 Western patients [14]. The authors aimed to assess whether adjuvant chemotherapy increases survival, measured by decreased risk of mortality. This meta-analysis suggested that adjuvant chemotherapy can provide a small overall survival benefit (OR 0.80, 95% CI = 0.66-0.97), corresponding to an absolute survival benefit of 4%. Subgroup analyses have shown a trend towards a larger effect when analysis was restricted to trials in which at least two-thirds of patients had lymph node-positive (N+) disease. Furthermore, a trend towards a lower relative risk was recorded for patients treated with anthracyclines [14].

In 2000, a meta-analysis conducted by GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente) and considering data from 3568 patients enrolled in 20 studies, showed a hazard ratio of death of 0.82 (95% CI = 0.75-0.89), representing an absolute survival effect of 2-4%. In a subgroup analysis, the authors did not detect any statistical difference between trials with or without the use of anthracycline-based therapy [15].

In 2002, Panzini et al. analysed data from 2913 patients enrolled in 17 randomised trials, with the exclusion of studies with incompletely resected patients. A statistically significant reduction in the risk of death was confirmed, with an odds ratio in treated patients of 0.72 (95% CI = 0.62-0.84) [16].

A fifth meta-analysis, including 21 randomised studies considering both Western and Asian patients, showed a significant survival benefit for patients who received adjuvant chemotherapy compared with controls (OR 0.84, 95%CI=0.74-0.96). However, it must be pointed out that when Western and Asian studies were analysed separately, no survival benefit was found for receiving adjuvant treatment in patients in the Western groups [17]. These findings are of crucial relevance as also stressed by Earle, who excluded Asian trials from his meta-analysis, in order to restrict the study to the most homogeneous group possible.

Gastric cancer appears to behave differently in the Asian setting, possibly due to different biology, aetiology or treatment. As the results of Asian adjuvant studies tend to favour the use of chemotherapy, their inclusion has supported the benefit of adjuvant chemotherapy and the difference between populations was well evidenced by Janunger [17] (Table 2).

Taken together, data from these meta-analyses seemed to suggest a small survival benefit for patients treated with adjuvant chemotherapy, but the relevance of these data to current clinical practice is limited due to lack of individual data collection, publication bias, and differences in patient populations and entry criteria of the trials. Furthermore, none of the published meta-analyses included adjuvant trials that used the third-generation chemotherapies (ie, cisplatin-based regimens), which appear to be more active in patients with advanced gastric cancer than previous regimens.

Adjuvant chemotherapy trials with cisplatin-containing regimens

Four adjuvant studies have evaluated the role of cisplatin-based regimens in the adjuvant setting. The Italian Trials in Medical Oncology (ITMO) group study reported the 5-year results of an adjuvant randomised study comparing surgery alone with gastric resection plus the adjuvant EAP (etoposide, adriamycin, platinum) chemotherapy regimen followed by 5-FU and leucovorin (according to the Machover schedule) in 274 patients, the majority of whom (90%) were N+. All patients underwent a subtotal or total gastrectomy with D2 dissection. The results of the trial were rather disappointing: adjuvant treatment produced only a small benefit in 5-year overall survival (OS) (52% in the treatment group versus 48% in the control group; P=0.869) and in disease-free survival (DFS) (49% in the treatment group versus 44% in the control group; P = 0.421), neither of which was statistically significant. Although this study failed to reach statistical significance, in the presence of widespread nodal involvement (N+ >6), the OS of the patients receiving chemotherapy was significantly better than that of the control patients (42% versus 20%). However, the ITMO trial was designed to detect a 15% difference in 5-year survival (from 30% in the control arm to 45% in the treatment arm) but 5-year overall survival in both groups was significantly better than that expected on the basis of previously published data [18].

The Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) study compared D1/D2 surgery alone against surgery followed by four cycles of PELF [cisplatin, epirubicin, leucovorin (LV) and 5-FU] in 258 patients with adenocarcinoma of the stomach at stages Ib, II, IIIa and b, or IV (T4N2M0). Adjuvant chemotherapy did not increase disease-free survival [hazard ratio (HR) of recurrence = 0.92, 95% CI = 0.66-1.27) or overall survival (HR of death=0.90, 95% CI = 0.64-1.26). The authors concluded that the study failed to provide proof of an effect of adjuvant chemotherapy with PELF on overall survival or disease-free survival. The estimated effect of chemotherapy (10% reduction in the hazard of death or relapse) was modest and consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents [19].

A GISCAD study compared surgery followed by the Machover regimen versus surgery followed by weekly PELF (PELFw). From January 1998 to January 2003, 400 gastric cancer patients at high risk for recurrence, including patients with serosal invasion (stage pT3N0) and/or lymph node metastasis (stage pT2 or pT3N+), were enrolled in the trial. Two hundred and one patients were randomly assigned to receive the PELFw regimen, consisting of eight weekly administrations of the PELF regimen with the support of filgrastim, and 196 patients were assigned to a regimen consisting of six monthly administrations of a 5-day course of 5-FU/LV. The objective of the trial was to assess whether adjuvant therapy with the more intensive PELFw regimen would result in improved survival in patients with locally advanced gastric cancer. Final analysis, performed after the planned follow-up (median follow-up 54 months), showed that both DFS and OS were virtually identical in the two study arms. It is important to note that the unexpectedly high survival rate in both treatment arms, possibly due to the high quality of the gastric surgery performed, limited the statistical power of the study to detect differences in outcomes [20].

The Federation Francophone de la Cancerologie Digestive (FFCD) randomised Phase III trial randomly assigned, after curative resection, 260 gastric cancer patients (79.7% N+) to postoperative chemotherapy (5-FU 800 mg/[m.sup.2] daily, 5-day continuous infusion) or surgery alone. Adjuvant chemotherapy was initiated before day 14 after resection. One month later, four 5-day cycles of 5-FU (1 g/[m.sup.2] per day) plus cisplatin (100 mg/[m.sup.2] on day 2) were administered every 4 weeks. The study was closed prematurely owing to poor accrual. At 97.8 months median follow-up, 5-and 7-year overall survival were 41.9% and 34.9% in the control group versus 46.6% and 44.6% in the chemotherapy group (P = 0.22). However, a risk reduction in recurrence was observed (0.70, 95% CI = 0.51-0.97; P=0.032) (Table 3) [21].

Adjuvant chemotherapy trials without cisplatin

In a planned combined analysis of two trials of the European Organization for Research and Treatment of Cancer (EORTC) and the International Collaborative Cancer Group (ICCG), enrolling 397 patients randomly assigned between surgery alone or surgery followed by fluorouracil, doxorubicin and methotrexate (FAMTX), or fluorouracil, epirubicin and methotrexate (FEMTX), no significant differences were found between the treatment and control arms for either DFS (HR = 0.98; P = 0.87) or OS (HR=0.98; P=0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively [22].

The Gruppo Oncologico Italia Meridionale (GOIM) group conducted a trial to evaluate the role of the non-cisplatin regimen ELFE (epirubicin, leucovorin, 5-fluorouracil and etoposide) as adjuvant therapy for radically resected gastric cancer patients. A total of 228 curatively resected patients were enrolled. All patients received a total or subtotal gastrectomy, with at least a D1 lymphadenectomy, and were randomly assigned to receive surgery alone or surgery followed by chemotherapy. With a median follow-up of 60 months, the 5-year OS was 48% in the treatment arm and 43.5% in the control arm (HR=0.91, 95% CI = 0.69-1.21; P = 0.610); the 5-year DFS was 44% in the treatment arm and 39% in the control arm (HR = 0.88, 95% CI = 0.66-1.17; P = 0.305). In node-positive patients the 5-year OS was 41% in the treatment arm and 34% in the control arm (HR=0.84, 95% CI = 0.69-1.01; P = 0.068), while the 5-year DFS was 39% in the treatment arm and 31% in the control arm (HR = 0.88, 95% CI = 0.78-0.91; P=0.051). These results do not support adjuvant treatment with the ELFE regimen in radically resected gastric cancer patients [23].

In a recent Phase III trial, the ACTS-GC group randomised 1059 patients with stage II or III gastric cancer, who underwent gastrectomy with extended (D2) lymph-node dissection, to S-1 monotherapy versus surgery alone. Overall survival at 3 years for all randomly assigned patients was 80.1% in the S-1 group and 70.1% in the surgery-only group (P=0.0024) [24]. This regimen was proposed as the standard treatment for stage II/III gastric cancer patients after curative D2 dissection in Japan. However, these results for the use of S-1 should be interpreted with caution, particularly with regard to the implications for clinical practice in a non-Japanese population, which can harbour different polymorphisms in genes crucial for metabolism of several chemotherapeutic agents (Table 4).

Adjuvant chemoradiotherapy

The importance of radiotherapy (RT) combined with chemotherapy (CT) in the adjuvant setting leads on to the possible role of RT and CT in reducing, respectively, local and distant relapse, which are frequently observed after radical surgery for gastric cancer.

The largest trial to evaluate the role of chemoradiotherapy as adjuvant treatment was the US Intergroup 0116. In this study, 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomised to surgery alone or to surgery plus postoperative chemoradiation. The adjuvant treatment consisted of 425 mg/[m.sup.2] 5-FU (bolus infusion) per day plus 20 mg/m2 of LV for five days, followed by 45 Gy in 25 fractions of 1.8 Gy over 5 weeks with bolus 5-FU and LV during the first and last week of the radiotherapy. This was followed 4 weeks later by two cycles of bolus 5-FU/LV.

The trial showed a statistically significant superiority of the chemoradiotherapy arm over surgery alone in median overall survival (36 months versus 27 months), 5-year relapse-free survival (31% versus 25%) and 5-year overall survival (40% versus 28.4%) [25]. However, toxicity was significantly higher with chemoradiation; about three-quarters of patients experienced grade 3/4 toxicity, and 17% of patients were unable to complete the treatment due to toxic effects. Moreover, the quality of surgical treatment in this study can be considered poor, as a substantial proportion of patients (54%) underwent a D0 resection, whereas only 10% of them received a D2 resection.

This trial showed that the chemoradiotherapy adjuvant approach was able to improve prognosis, mainly by lowering the incidence of local relapse (from 29% to 19%), while a limited effect or no effect was seen on metastatic diffusion. Based on these considerations, the results of the INT-0116 trial could also be interpreted by the hypothesis of having treated residual disease by chemoradiotherapy in a significant subgroup of patients. Taken together, these findings obviously question the role of adjuvant chemoradiotherapy as a standard of practice in all gastric cancer patients, whereas its role could be that of partial compensation for inadequate surgery.

Regarding lymphadenectomy, a general agreement seems to have been achieved about a so-called 'over-D1 lymphadenectomy' (D1 dissection and retrieval of at least 25 nodes) on the basis of the finding that the probability of accurate assessment of lymph node status increases with the number of nodes resected, with a plateau reached at 20-25 nodes. However, although this recommendation addresses the principle that lymph nodes are regarded as indicators rather than governors of disease, several clinical data indicated that resection of more than 25 lymph nodes could have a major impact on the global outcome of patients who underwent apparent radical surgery for gastric cancer. This improvement could be mainly due to a reduction in local recurrences [5,26].

Conclusions and perspectives

Despite the large number of trials, the evidence supporting the usefulness of adjuvant chemotherapy in curatively resected gastric cancer patients is not yet definitive and no standard adjuvant chemotherapeutic regimen has been established. However, independent of the patient population or the practice location, surgery alone is no longer the standard treatment for patients with resectable gastric cancer. Regardless of the type of surgery or the timing of the adjuvant treatment, the use of combined treatments improves the prognosis for patients with this disease [27-29].

Until now, available data have seemed to suggest a possible algorithm that can be useful in the management of radically resected gastric cancer (Table 5).

It is worthwhile pointing out the particularity of adenocarcinoma of the oesophagogastric junction, which shows a worse prognosis than that of adenocarcinoma in other parts of the stomach. Despite this fact, emerging data from randomised trials suggest that an aggressive approach, such as perioperative treatment, could improve the outcome of oesophagogastric junction cancer patients. In the MAGIC trial, subgroup analysis revealed a particularly evident survival benefit from perioperative ECF for patients affected with cancer of the oesophagogastric junction.

The advent of new regimens, inducing higher response rates, indicates that gastric cancer is a chemosensitive tumour; therefore, from a theoretical point of view, regimens with higher activity may have more efficacy as adjuvant therapy.

Trials that are exploring ways of improving combined treatment strategies for resectable gastric cancer include the United Kingdom National Cancer Research Institute ST03 trial of perioperative epirubicin, cisplatin and capecitabine (with or without the anti-vascular endothelial growth factor antibody bevacizumab) and the US Cancer and Leukemia Group B protocol 80101 trial, which is testing a postoperative adjuvant strategy of epirubicin, cisplatin and fluorouracil chemotherapy before and after chemoradiation.

References

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[7.] Boige V, Pignon J, Saint-Aubert B et al. Final results of randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of the stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial. ASCO 2007, Abstr 4510.

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[13.] Pignon JP, Ducruex M and Rouger P. Meta-analysis of adjuvant chemotherapy in gastric cancer: a critical reappraisal. J Clin Oncol, 1994, 12, 877-878.

[14.] Earle CC and Maroun JA. Adjuvant chemotherapy after resection for gastric cancer in non-Asian patients. Revisiting a meta-analysis of randomized trials. Eur J Cancer, 1999, 35, 1059-1064.

[15.] Mari M, Floriani I, Tinazzi A et al. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis for published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente). Ann Oncol, 2000, 11, 837-843.

[16.] Panzini I, Gianni L, Fattori PP et al. Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous metaanalyses. Tumori, 2002, 88, 21-27.

[17.] Janunger KG, Hafstrom L and Glimelius B. Chemotherapy in gastric cancer: a review and updated meta-analysis. Eur J Surg, 2002, 168, 597-608.

[18.] Bajetta E, Buzzoni R, Mariani L et al. Adjuvant chemotherapy in gastric cancer: 5-year results of a randomized study by the Italian Trials in Medical Oncology (ITMO) Group. Ann Oncol, 2002, 13, 299-307.

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Eva Galizia, Mario Scartozzi, Rossana Berardi, Mirco Pistelli, Alessandro Bittoni and Stefano Cascinu

Department of Medical Oncology, AO Ospedali Riuniti-Universita Politecnica delle Marche, Ancona, Italy

Correspondence to: Stefano Cascinu (email: cascinu@yahoo.com)
Table 1: Perioperative trials

Trial (year)           Number of   Treatment   Hazard ratio
                       patients                for overall survival

MAGIC (2006) [4]       504         ECF         0.75 (0.60-0.93)

FFCD 9703 (2007) [7]   224         5-FU+CDDP   0.69 (0.50-0.95)

Trial (year)           P           5-year
                                   survival rate (%)

MAGIC (2006) [4]       0.009       36 versus 23

FFCD 9703 (2007) [7]   0.02        38 versus 24

CDDP, cisplatin ; CI, confidence interval; ECF, epirubicin,
cisplatin and 5-FU; 5-FU, 5-fluorouracil

Table 2: Results of meta-analyses

                                               Hazard ratio
                                               for overall
Author (year)          Number of   Number of   survival
                       studies     patients    (95% CI)

Hermans (1993) [11]    11          2096        0.82 (0.78-1.08)

Earl (1999) [14]       13          1990        0.80 (0.66-0.97)

Mari (2000) [15]       20          3568        0.82 (0.75-0.89)

Panzini (2002) [16]    17          2913        0.72 (0.62-0.84)

Janunger (2002) [17]   21          3962        0.84 (0.74-0.96)

                       Reduction of
Author (year)          Mortality (%)

Hermans (1993) [11]    18

Earl (1999) [14]       20

Mari (2000) [15]       18

Panzini (2002) [16]    28

Janunger (2002) [17]   C16I, Confidence interval

Table 3: Results of meta-analyses

                                 Number of
Author/group (year)              patients    Treatment

Bajetta/ITMO (2002) [18]         274         EAP [right arrow] 5-FU/LV
Di Costanzo/GOIRC (2008) [19]    258         PELF
Cascinu/GISCAD (2007) [20]       400         PELFw
Bouche/FFCD (2005) [21]          260         5-FU CI [right arrow]
                                               5-FU/CDDP

                                 Hazard ratio for
Author/group (year)              death (95% CI)

Bajetta/ITMO (2002) [18]         0.93 (0.65-1.34)
Di Costanzo/GOIRC (2008) [19]    0.90 (0.64-1.26)
Cascinu/GISCAD (2007) [20]       0.95 (0.70-1.29)
Bouche/FFCD (2005) [21]          0.74 (0.54-1.02)

CI, Confidence interval

Table 4: Adjuvant chemotherapy trials without cisplatin-containing
regimens

Author/group          Number of           Treatment
(year)                patients

Nitti/EORTC           397                 FAMTX (or FEMTX)
(2006) [22]

De Vita/GOIM          228                 ELFE
(2007) [23]

Sakuramoto/ACTS-GC    1059                S-1
(2008) [24]

Author/group          Hazard ratio for    5-year survival rate
(year)                death (95% CI)      (%)

Nitti/EORTC           0.98 (0.72-1.24)    43 versus 44
(2006) [22]

De Vita/GOIM          0.91 (0.69-1.21)    48 versus 43.5
(2007) [23]

Sakuramoto/ACTS-GC    0.68 (0.52-0.87)    80.1 versus 70.1
(2008) [24]                               (3-year survival rate)

CI, Confidence interval

Table 5: Suggested algorithm after radical surgery
for gastric cancer

p N status   Number of                       Treatment
             resected
             lymph nodes

NO           [greater than or equal to] 15   Follow-up
             < 15                            Adjuvant chemoradiotherapy

N+           [greater than or equal to] 25   Follow-up
             < 25                            Adjuvant chemoradiotherapy
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Author:Galizia, Eva; Scartozzi, Mario; Berardi, Rossana; Pistelli, Mirco; Bittoni, Alessandro; Cascinu, Ste
Publication:Advances in Gastrointestinal Cancer
Date:Dec 1, 2008
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