Clinical trial breaks new ground in the management of stage II colorectal cancer

Colorectal cancer is the third most common type of newly diagnosed cancer in Australia. More than 15,000 Australians are told they have colorectal cancer every year. It is also the second most deadly, claiming more than 5000 lives every year.

The current standard of care for non-metastatic colorectal cancer is surgery, with histopathological staging (stage I, II, III, IV) informing whether adjuvant chemotherapy should also be given. For patients with stage III colorectal cancer, adjuvant chemotherapy is routinely used, as cure rates are only 50-60%, and chemotherapy increases survival by 15-20%. However, in stage II cancer, the cure rate is much higher (80%) and adjuvant chemotherapy improves outcomes by only a very small amount. Even when restricted to stage II patients with adverse histological features, the benefit of treatment is still very small – for every 100 stage II patients receiving chemotherapy, only three or four recurrences are prevented, yet all are being exposed to the inconveniences and side effects. We need a better way to identify, in advance, the unlucky 20% of stage II patients destined to relapse, and then we could restrict chemotherapy treatment to this sub-group.

The landmark circulating tumour DNA analysis informing adjuvant chemotherapy in stage II colon cancer (DYNAMIC) clinical trial has helped address this clinical dilemma. Circulating tumour DNA (ctDNA) are very small pieces of cancer DNA that are circulating free in the bloodstream, that have been shedded by cancer persisting somewhere in the body. They should not be present in the blood of patients without cancer. Patients with colorectal cancer who have ctDNA found in their blood following surgery have previously been shown, by a landmark Australian study led by Jeanne Tie, to have a very high risk of cancer recurrence.

DYNAMIC is the follow-on study from this research, and is the first study to use ctDNA to direct adjuvant therapy in colorectal cancer, demonstrating that a ctDNA-guided approach can reduce the use of adjuvant chemotherapy without compromising the risk of cancer recurrence in stage II colorectal cancer patients.

The trial randomly assigned stage II colorectal cancer patients to have their treatment decisions guided by either ctDNA results or standard clinicopathological features. For the ctDNA guided management group, a ctDNA-positive result at four or

15,000+ Australians are diagnosed with colorectal cancer every year seven weeks after surgery prompted adjuvant chemotherapy treatment. Patients who were ctDNA-negative were not treated. This study aimed to reduce the amount of chemotherapy administered to stage II patients, without compromising outcomes.

This is exactly what was found – chemotherapy use was halved, without compromising outcomes.

Even though ctDNA positive patients are known to have a very high risk of cancer recurrence, in this study, when these patients received chemotherapy, outcomes were similar to the good outcomes seen in the standard arm patients (where doctors did not receive ctDNA results and offered chemotherapy to all patients with adverse histological features). In addition, patients who were ctDNA-negative had a very low risk of recurrence (93%, two-year recurrence free rate) even without the use of adjuvant chemotherapy.

Principal Investigator and co-author of the New England of Journal Medicine paper, Associate Professor Jeremy Shapiro led the trial at Cabrini.

“It’s great to see Australian researchers leading the way in this landmark study to allow better selection of chemotherapy, limiting treatment to those patient’s who really need it,” said A/Prof Shapiro (of DYNAMIC).

“The challenge now, is how to bring this important advance to the clinic. This study used a gold standard ctDNA test, which is costly, and with results that take several weeks to finalise. There are simpler and cheaper tests, with faster turnaround times, that are in advanced testing, but will they be as reliable? Only time –and more clinical trials – will tell.”

Colorectal cancer claims the lives of more than

5000 Australians every year