45th Annual Meeting of the American Society of Clinical Oncology (ASCO).
The 45th American Society of Clinical Oncology (ASCO) Annual Meeting was held at the Orange County Convention Center, Orlando, Florida, from 29 May to 2 June, 2009. With over 30,000 attendees from all over the world, ASCO continues to be the world's premier cancer conference, a dynamic force in international cancer research, providing a platform for cutting-edge scientific research and educational development in oncology. The theme for 2009 was personalising cancer care. The meeting showcased over 4000 abstracts, of which a selection of gastrointestinal carcinomas, are highlighted in this report.
The ToGA trial
No doubt the conference's biggest news, hailed as 'practice-changing' by outgoing ASCO president, Richard L Schilsky, was the ToGA trial of trastuzumab (Herceptin) for patients with advanced gastric cancer.
ToGA (Trastuzumab with chemotherapy in HER2-positive advanced Gastric cancer) is the first randomised, prospective, multi-centre, phase III trial to study the efficacy and safety of anti-HER2 therapy in advanced gastric cancer, and showed that treatment with trastuzumab and chemotherapy is superior to treatment with chemotherapy alone.
Gastric cancer is the fourth most commonly diagnosed cancer in the world and the seventh most common cause of cancer-related death in the UK. Approximately one million new cases are identified worldwide every year. Patients are often diagnosed late as they do not show symptoms early on in the disease.
The ToGA study was conducted in 24 countries across Europe, Asia, Australia, South and Central America, and South Africa . Of 3807 patients with gastric cancer enrolled, 22.1% were HER2-positive. Of these patients with HER2-positive gastro-oesophageal and gastric adenocarcinoma (locally advanced, recurrent, or metastatic), 594 were randomised to receive:
* either trastuzumab (6 mg/kg every 3 weeks until progression) plus chemotherapy (5-FU or capecitabine and cisplatin, three times a week for six cycles);
* or chemotherapy alone.
The primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival, time to progression, duration of response, and safety. The trial was stopped early (after a median follow-up of 17 months) because of the benefit seen.
There was a significant improvement in median overall survival of 2.4 months in the trastuzumab group, from 11.1 months in the chemotherapy group to 13.5 months in the trastuzumab group [hazard ratio (HR), 0.74; P=0.0048].
The addition of trastuzumab also improved all the secondary end points, including overall response rate (increased from 34.5% to 47.3%; P=0.0017), complete response rates (increased from 2.4% to 5.4%; P=0.0599) and progression-free survival (increased from 5.2 months to 6.7 months; P=0.002).
It was suggested that overall survival in both groups was longer than expected because a large proportion of the patients were Asian, a group that has better prognosis.
Patients with tumours exhibiting high levels of HER2 experienced even greater benefit from the addition of trastuzumab.
The most common side effects were diarrhoea (4.8%) and febrile neutropenia (3.4%). Treatment-related deaths were one in the chemotherapy group and three in the trastuzumab group. Previously, treatment with trastuzumab has been associated with cardiac problems; however, this was not apparent in ToGA 'probably because this patient cohort was not exposed to anthracyclines,' stated Professor Eric Van Cutsem.
Symptomatic congestive heart failure occurred at a similar rate in both groups. Asymptomatic left ventricular ejection fraction decreases were reported in 4.6% of patients in the combination arm and 1.1% in the chemotherapy-alone arm.
Whilst overall 22% of patients were HER2-positive, HER2 over-expression appears to vary with tumour site and histology, higher rates being found at the oesophageal gastric junction (35%) and in those of intestinal pathology (33%).
The trial used both fluorescence in situ hybridisation (FISH) and in situ hybridisation (ISH) techniques to test for HER2. Applying the ASCO 2007 guidelines for HER2 testing for breast cancer, only 256 patients were deemed HER2 positive. In this select group, overall survival increase was even greater, from 12.3 months to 17.89 months (HR, 0.58).
HER2 is a protein which acts as a receptor regulating cell growth, survival and angiogenesis. Cancers which over-express HER2 therefore grow at a faster rate and are associated with increased rates of recurrence and worse prognosis. Trastuzumab is a monoclonal antibody which binds to HER2 and inactivates it.
Trastuzumab has been shown to improve response rates, overall survival and disease-free survival in both early and late HER2-positive breast cancer. It was approved for treatment of late (metastatic) HER2-positive breast cancer in 2000, and in early HER2-positive breast cancer in 2006 in the EU.
Experts at ASCO agreed that all patients with advanced gastric cancer should be tested for HER2, and if found to be positive should be treated with trastuzumab in addition to their usual chemotherapy.
Unresectable, asymptomatic mCRC does not require primary tumour excision
Another gastrointestinal abstract which made a big impression was a retrospective study looking into whether surgical excision of the primary tumour in patients with metastatic colorectal cancer was necessary .
From 2000 through 2006, 233 consecutive patients were identified with synchronous metastatic CRC and an unresected primary tumour. All patients received oxaliplatin- or irinotecan-based, triple-drug chemotherapy with or without bevacizumab as their initial treatment. The incidence of subsequent use of surgery, radiotherapy, and/or endoluminal stenting to manage primary tumour complications was recorded.
It was previously thought necessary to remove the primary tumour to prevent complications such as obstruction, perforation and bleeding. However out of 233 patients in this study, 217 (93%) never required surgical palliation of their primary tumour.
Of the 16 (7%) who did require intervention (either for obstruction or perforation), procedures were successful in 14 of the cases, suggesting that delaying surgery did not increase risk. Two of the patients requiring intervention died as a result of surgery, giving a mortality of 0.8% for the total population, which compares well with the 1-5% operative mortality associated with surgery up front. Ten patients in the study did require non-operative intervention in the form of stenting or radiotherapy.
Of the 213 patients (89%) who did not require any direct management of their primary, 47 (20%) underwent elective resection at the time of metastasectomy and 8 (3%) during laparotomy for hepatic artery infusion pump placement.
Therefore it is possible to avoid surgery in the majority of patients. Not only does this avoid the morbidity and mortality of surgery, it also allows chemotherapy treatment to begin earlier.
It was also noted that rates of intervention did not increase with a rectal site of primary tumour and high tumour burden, as previously thought.
Dr Nicholas Petrelli, of Thomas Jefferson University, Philadelphia, who chaired the meeting, noted that more data was needed, and this should be provided by the results of the National Surgical Adjuvant Breast and Bowel project, the results of which are expected to be available by the end of the year.
Whilst the findings in this study are not new, they do provide published evidence to support this conservative line of management.
No difference between adjuvant 5-FU/FA and gemcitabine in pancreatic cancer
The European Study Group for Pancreatic Cancer-3 trial [ESPAC-3 (v2)] was an international multicentre study set up to compare adjuvant chemotherapy with 5-fluorouracil/folinic acid (5-FU/FA) and gemcitabine (GEM) to see if either produced significantly longer survival rates .
Previous trials have shown that both adjuvant 5-FU/FA and gemcitabine provide improved survival in post-operative patients when compared with no chemotherapy (ESPAC-1 trial and CONKO-001 trial).
From July 2000 to January 2007, a total of 1088 patients from 16 countries with pancreatic ductal adenocarcinoma with R0 or R1 (35%) resection margins were randomised within 8 weeks of surgery to receive treatment with either 5-FU/FA or gemcitabine for 6 months. Of these, 72% were node positive, and 25% had poorly differentiated tumours.
The primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival and quality of life. Median follow-up was 34 months.
There was no significant difference in median survival between the two groups (5-FU/FA, 23.0 months versus GEM at 23.6 months).
The results of ESPAC-3(v2) therefore prove that both 5-FU/FA and gemcitabine are equally effective in the adjuvant setting for the treatment of pancreatic ductal carcinoma.
However, treatment with 5-FU/FA was associated with more side effects than gemcitabine, including:
* Grade 3/4 stomatitis (5-FU/FA, 10% versus GEM, 0%)
* Diarrhoea (5-FU/FA, 13% versus GEM, 2%)
* Treatment-related hospitalisations (5-FU/FA, 10% versus GEM, 3.5%)
This higher rate of side effects is thought to be due in part to the outdated regime used for 5-FU/FA in the study. It was noted that due to fewer side effects, gemcitabine currently remains the drug of choice.
As the two drugs have different mechanisms of action, the next trial will look at combination therapy to see if it is superior to monotherapy. ESPAC-4 will compare treatment with gemcitabine alone to gemcitabine in combination with the updated and less toxic oral 5-FU, capecitabine.
ASCO 2009 was once again the year's largest international cancer meeting, with so many high-quality presentations spanning all cancer types and associated research data. See www.asco.org for further information and abstracts.
[1.] Van Cutsem E, Kang Y, Chung H et al. Efficacy results from the ToGA trial: A Phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). J Clin Oncol, 2009, 27(18s), Abstr. LBA4509.
[2.] Poultsides EL, Servais LB, Saltz S et al. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol, 2009, 27(18s), Abstr. CRA4030.
[3.] Neoptolemos M, Buchler DD, Stocken P et al. ESPAC-3(v2)--A multicenter, international, open-label, randomized controlled Phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma. J Clin Oncol, 2009, 27(18s), Abstr. LBA 4505.
Correspondence to: Vanessa Brown
Vanessa Brown (1) and Sascha Dua (2)
(1) London Deanery, London, UK, (2) Royal Free Hospital, London, UK
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|Title Annotation:||Conference Report|
|Author:||Brown, Vanessa; Dua, Sascha|
|Publication:||Advances in Gastrointestinal Cancer|
|Article Type:||Conference news|
|Date:||Jun 1, 2009|
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