'25 at 25': Transforming treatment for gastroesophageal cancer

10 May 2024

As we celebrate 25 years of the MRC Clinical Trials Unit at UCL, we reflect on our clinical trials and studies which have made the biggest difference to patients. Our OE02 and MAGIC (ST02) trials transformed treatment for gastroesophageal cancer with the addition of chemotherapy to the standard-of-care. A combination of surgery and chemotherapy is now widely used across the world, leading to more favourable odds of survival.

In the early 1990s, the outlook for people diagnosed with stomach or oesophageal cancer was generally poor. The main treatment was surgery to remove the tumour and potentially cure the cancer, but this was only successful for a relatively small number of people.

Before the OE02 and MAGIC trials, smaller studies had suggested that it may be helpful to give chemotherapy before surgery to people with gastroesophageal cancers, as it might help them live longer. This was because pre-operative chemotherapy might shrink the tumour, making it easier to remove through surgery. Pre- and post-operative chemotherapy might also remove any undetected disease and therefore slow down or prevent the cancer returning in future.

OE02 and MAGIC put these hypotheses to the test with larger numbers of participants.

The OE02 trial opened to recruitment in 1992 and closed in 1998, enrolling 802 participants with operable oesophageal cancer, meaning the tumour could be removed with surgery. When the trial began, only around one in five people with oesophageal cancer lived for more than two years after their operation.  

Researchers randomly assigned participants to receive either surgery only (the standard-of-care at the time) or chemotherapy followed by surgery.

In 2002, the team published the main results in The Lancet. OE02 found that pre-operative chemotherapy did in fact improve survival for people with oesophageal cancer. On average, participants who had pre-operative chemotherapy lived for around 16.8 months compared to 13.3 months for those who only had surgery.

The MAGIC trial opened in 1994 and finished recruiting in 2002. It included 503 participants with operable stomach, gastroesophageal junction or lower oesophageal cancer. The trial compared participants who had surgery only with those who had chemotherapy before and after surgery.

Results from MAGIC also revealed that chemotherapy helped people with gastroesophageal cancers live longer. Adding peri-operative chemotherapy to surgery increased the five-year survival rate from 23 in 100 to 36 in 100. This corresponded to a 25% reduction in the risk of death.

The main results paper for MAGIC, which was published in the New England Journal of Medicine in 2006, remains one of the MRC CTU at UCL’s most cited cancer publication with more than 4,500 citations.

Using chemotherapy to treat gastroesophageal cancer was very uncommon before OE02 and MAGIC, but these pioneering trials were drivers of change. With the availability of high-quality evidence from large clinical trials, chemotherapy soon became part of the standard-of-care, and future clinical trials in this area used surgery and chemotherapy as their control arm.

Many surgeons had worried about postponing surgery until after chemotherapy, but they instead found that shrinking the tumour beforehand actually made the operation easier. 

People with gastroesophageal cancers are now routinely offered chemotherapy as well as surgery. This is recommended by treatment guidelines across the world, including the National Institute for Health and Care Excellence in the UK, the European Society for Medical Oncology (ESMO), the National Comprehensive Cancer Network in the USA and Chinese Society of Clinical Oncology.

Stomach and oesophageal cancers are still challenging to treat. Vague symptoms which are not specific to cancer mean that many people are diagnosed at a late stage when the cancer is no longer operable.

But thanks to the addition of chemotherapy before and/or after surgery to the standard-of-care, people diagnosed with operable gastroesophageal cancers now have a much better chance of long-term survival.

In at the years 2010-2014, the International Cancer Benchmarking Partnership found that the UK’s five-year survival rate for oesophageal cancer in patients under 75 years old had almost doubled since the 1995-1999 period. Comparing the same periods, five-year survival for stomach cancer in patients under 75 years old had increased by almost 50%.

OE02 and MAGIC opened more than 30 years ago, but the story of these trials is still yet to reach its end. Biological samples kindly donated by trial participants have opened new avenues of translational research, on which the MRC CTU at UCL has collaborated closely with the Royal Marsden Hospital and the University of Leeds.

For example, in one study using tissue samples collected from MAGIC participants, researchers found that the level of response to pre-operative chemotherapy was not an indicator of whether the cancer was likely to return. However, whether the cancer had spread to the lymph nodes was a good predictor.

Another translational study was a 2019 meta-analysis which pooled individual participant data from MAGIC along with another trial called CLASSIC. The meta-analysis found that patients whose tumours show genetic changes called microsatellite instability do well when treated with surgery only, even without perioperative chemotherapy. These patients therefore could avoid chemotherapy as there is no added benefit.

As recently as October 2023, researchers presented results from OE02 at the 2023 ESMO Congress. The study looked at genetic differences which are associated with better survival in early oesophageal cancer.

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