Annual meeting of the American Society of Clinical Oncology (ASCO), 2007.

Introduction

This conference report covers the most important trial results relating to gastrointestinal cancers, presented at the 2007 ASCO annual meeting held in Chicago. Results of trials involving molecular targeted agents were again prominent in both upper and lower gastrointestinal malignancies.

Oesophagogastric cancer

In oesophagogastric cancer, two Phase III trials evaluating pre-operative treatment approaches were presented: the Federation Francophone de Cancerologie Digestive (FFCD) 9703 trial evaluated peri-operative chemotherapy versus surgery alone in patients with adenocarcinoma of the stomach and lower oesophagus; and the Preoperative Chemotherapy or Radiochemotherapy in Esophago-gastric Adenocarcinoma Trial (POET) study evaluated pre-operative chemotherapy versus chemoradiotherapy in locally advanced oesophagogastric adenocarcinoma.

The aim of the FFCD 9703 study (Valerie Boige; Abstr. 4510) was to determine whether peri-operative chemotherapy improves the outcomes of patients with resectable oesophagogastric cancer. Enrolled patients had adenocarcinoma of the lower third of the oesophagus or oesophagogastric junction deemed suitable for curative resection. Randomisation was to receive either two to three cycles of pre-operative chemotherapy and three to four cycles of post-operative chemotherapy (C+S) or to surgical resection alone (S). The chemotherapy delivered consisted of cisplatin 100 mg/[m.sup.2] day 1 and 5-flourouracil (5FU) 800 mg/[m.sup.2] continuous infusion on days 1-5 every 28 days. The primary endpoint was overall survival. Of the 113 patients in the C+S arm, 98 (87%) received pre-operative chemotherapy and 109 (97%) underwent resection. In the surgery alone arm, 99% (110/111) of patients underwent resection. Post-operative morbidity was not increased in the chemotherapy arm. The R0 resection rate was 73% in the S arm versus 84% in the C+S arm (P=0.04). A total of 54 patients in the C+S arm went on to receive post-operative chemotherapy. Overall survival was significantly improved in the chemotherapy arm with a hazard ratio of 0.69 [95% confidence interval (CI), 0.50-0.95; log rank P=0.021] translating to a 14% improvement in 5-year overall survival. The results seen in this trial are in keeping with the Medical Research Council's (MRC) MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) and OEO2 trials which demonstrated a 13% and 9% improvement in 5-year survival, respectively, although in slightly different patient groups.

The POET study (Michael Stahl; Abstr. 4511) investigated the potential benefit of pre-operative chemoradiotherapy as compared to pre-operative chemotherapy alone in patients with locally advanced tumours involving the oesophagogastric junction (Siewert type I-III). The study planned to recruit 354 patients but closed early, as a result of poor accrual, with only 119. Patients in both arms received two initial 6-week cycles of cisplatin/5FU/leucovorin (LV) (PLF) chemotherapy (cisplatin 60 mg/[m.sup.2] on days 1, 15 and 29, and 5FU and LV 2 g/[m.sup.2] and 500 mg/[m.sup.2], respectively, on days 1, 8, 15, 22, 29 and 36). In the chemotherapy alone arm, patients received a further 3-week cycle of PLF, whereas patients in the chemoradiotherapy arm received 15x2 Gy fractions given over 3 weeks with concurrent cisplatin/etoposide (PE) chemotherapy (cisplatin 50 mg/[m.sup.2] on days 2 and 8, and etoposide 80 mg/[m.sup.2] on days 3-5). A total of 88% and 82% of patients underwent surgery in the chemotherapy and chemoradiotherapy arms, respectively. Hospital mortality was higher in the chemoradiotherapy arm at 10.2% versus 3.8%. Three-year overall survival was 47.4% and 27.7% (P=0.06) in the chemoradiotherapy and chemotherapy arms, respectively, with benefit in local disease control demonstrated in the chemoradiotherapy arm. This study, undertaken in a high-risk patient subgroup, demonstrated a trend towards benefit with the use of pre-operative chemoradiation but at the cost of greater morbidity and hospital mortality. A variety of pre- and postoperative treatment strategies continue to be evaluated in ongoing studies.

Pancreatic cancer

The results of two important Phase III trials evaluating the impact of molecular targeted antibody agents in pancreatic cancer were presented. The Cancer and Leukemia Group B (CALGB) 80303 study (Hedy Lee Kindler; Abstr. 4508) was a double-blind, placebo-controlled, Phase III study evaluating the benefit of bevacizumab when given in combination with standard gemcitabine chemotherapy. A total of 602 patients with unresectable pancreatic cancer were randomly assigned to receive either gemcitabine/bevacizumab or gemcitabine/placebo. The primary endpoint was overall survival. An interim analysis undertaken in June 2006 revealed that a futility boundary had been crossed and therefore the study was unblinded. There were no differences in response rate, progression-free survival or overall survival between the arms. Although the combination of gemcitabine and bevacizumab appears to have no role in the treatment of pancreatic cancer, ongoing trials (such as AVITA) are evaluating the possible benefit from combining targeted agents. A study undertaken by the southwest Oncology Group (SWOG S0205) (Philip A Philip; Abstr. LBA4509) evaluated the potential benefit of cetuximab when given in combination with standard gemcitabine therapy. The median overall survival was 5.9 and 6.4 months (hazard ratio, 1.09; P=0.14) in the gemcitabine and gemcitabine/cetuximab arms, respectively. Although there was no statistical difference in outcomes, there did appear to be some separation of the survival curves indicating a possible small increase in activity with the addition of cetuximab; this would be in keeping with the modest but statistically significant survival benefit that has been seen with the addition of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib in the National Cancer Institute of Canada Clinical Trials Group PA.3 study [1].

Hepatocellular carcinoma

The Sorafenib HCC Assessment Randomised Protocol (SHARP) trial (Joseph Llovet; Abstr. LBA1) evaluated the activity of the multi-targeted kinase inhibitor sorafenib in hepatocellular carcinoma (HCC). In this placebo-controlled study, 602 patients with advanced HCC who had received no previous systemic therapy were randomly assigned to receive either oral sorafenib 400 mg twice daily or placebo. The primary endpoint was overall survival. A majority of recruited patients were from Europe, 20% had prior surgery and ~40% had prior loco-regional therapy. An improvement in overall survival was seen in the sorafenib arm with a median survival of 10.7 months as compared to 7.9 months in the placebo arm, and a hazard ratio of 0.69 (95% CI, 0.55-0.88; P=0.00058). It is important to note that the benefit in overall survival was achieved with a low radiological response rate of 2.3% in the sorafenib arm. The most common adverse events were diarrhoea, anorexia and hand-foot skin reaction, although the rate of grade 3/4 reactions was low. Until now there has been no widely accepted standard therapy for patients with advanced HCC, and sorafenib represents a new treatment choice in this disease. A further study is evaluating the benefit of sorafenib when given in addition to doxorubicin chemotherapy; results from this study are due to be presented at the European Cancer Conference (ECCO) in 2007.

Colorectal cancer

In 2003 the first randomised data demonstrating the clinical activity of cetuximab in chemorefractory colorectal cancer were presented at the ASCO annual meeting [2]. This year we heard about data relating to the first-line activity of cetuximab in advanced colorectal cancer. The Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial (Eric Van Cutsem; Abstr. 4000) examined the efficacy and toxicity of cetuximab when given in addition to 5-FU/LV/irinotecan (FOLFIRI) chemotherapy. A total of 1202 patients with EGFR-expressing metastatic colorectal cancer were randomly assigned to receive either FOLFIRI according to a standard schedule or FOLFIRI/cetuximab. The primary endpoint was progression-free survival. As expected, patients receiving cetuximab had a significantly higher rate of skin reaction, but also showed a slightly higher incidence of grade 3/4 diarrhoea (15.2% versus 10.5%). Otherwise toxicities between the two treatment arms were comparable.

The median progression-free survival was 8.0 and 8.9 months in the FOLFIRI and FOLFIRI/cetuximab arms, respectively, with a hazard ratio of 0.85 (95% CI, 0.726-0.998; stratified log rank P=0.0479). It is interesting that there appeared to be no separation of the progression-free survival curves during the first 6 months of therapy. At 1 year, the progression-free survival rates were 23% and 34% in the FOLFIRI and FOLFIRI/cetuximab arms, respectively. Patients receiving cetuximab demonstrated a higher radiological response of 46.9% versus 38.7%. This improved response rate translated to an increased proportion of patients able to undergo an attempt at curative resection in the cetuximab arm (6% versus 2.5%). As in previous studies evaluating EGFR-targeted agents, a clear correlation between severity of skin rash and survival was seen. From the progression-free survival curves it would appear that the benefit of cetuximab is restricted to a subgroup of patients. The identification of predictive markers for response to EGFR-targeted agents has been the focus of much ongoing research. Current evidence suggests that EGFR gene copy number and KRAS mutational status may be important determinants of response to EGFR-targeted therapies. The results of a retrospective analysis (Giovanna Finoocchiaro; Abstr. 4021) conducted across five Italian institutes gave further support to this theory.

New information on the role of chemotherapy in the management of patients with resectable liver metastasis was gained from the European Organisation for Research and Treatment of Cancer (EORTC) 40983 trial (Bernhard Norlinger; Abstr. LBA5). In this study, patients with metastatic liver disease limited to fewer than four deposits and considered resectable, were randomly assigned to either six cycles of pre-operative 5-FU/LV/oxaliplatin (FOLFOX) chemotherapy and a further six cycles of postoperative FOLFOX or to surgery alone. The primary endpoint was improvement in progression-free survival. A similar proportion of patients in each arm underwent liver resection with 83.0% in the pre-operative chemotherapy arm and 83.5% in the surgery alone arm. Post-operative complications were more common in the chemotherapy arm with a rate of 25.2% compared to 15.9% in the surgery alone arm. A total of 63.2% of the chemotherapy arm went on to receive post-operative chemotherapy. Patients receiving peri-operative chemotherapy showed an improvement in progression-free survival. On an intention-to-treat basis, the improvement in progression-free survival did not reach significance with a hazard ratio of 0.79 (95% CI, 0.62-1.02; P=0.058). However, when considering only those patients who underwent resection, the difference was significant with a hazard ratio of 0.73 (95% CI, 0.55-0.97; P=0.025); this translates to an improvement in 3-year progression-free survival of 9.2%. These results indicate the potential utility of this treatment approach in patients with resectable liver metastasis; however, during the discussion caution was advised particularly in relation to the potential for chemotherapy-induced liver injury and associated increases in surgical morbidity.

Conclusions

In oncological practice, progress is on the most part achieved through small incremental steps and the results presented at ASCO this year move us slightly further along our path to improving patient outcomes. Sorafenib represents a new treatment option for patients with advanced HCC. In the treatment of patients with oesophagogastric cancer we have seen how pre-operative chemoradiotherapy may improve outcomes, but at the cost of increased treatment-related morbidity. Similarly in the management of patients with resectable colorectal cancer liver metastases, improved outcomes may be achieved with the use of pre-operative chemotherapy, but again at a cost of increased surgical morbidity. Over the coming years our trials will continue to focus efforts on optimising treatment strategies according to individual patient risk and therefore minimising the potential for treatment-related morbidity.

All abstracts can be found in a special supplement in J Clin Oncol, 2007, 25 (Suppl 18).

Reference

[1.] Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 2007, 25, 1960-1966.

[2.] Cunningham D, Humblet Y, Siena S et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecanrefractory metastatic colorectal cancer (MCRC). Proc ASCO, 2003, 22, Abstr. 1012.

David Watkins

Department of Medicine, Royal Marsden Hospital, London and Sutton, UK

Correspondence to: David Watkins (email: [e-mail])