Colorectal cancer is one of the most common cancers in Australia and the second leading cause of cancer deaths.
About 14,000 new cases of colorectal cancer are diagnosed each year and about 4,000 are or become metastatic. It is a disease affects people of all ages, although its risk increases with age.
Twenty years ago the average prognosis for colorectal cancer was six months. With the introduction of chemotherapy this improved to 12 months, then the use of combinations and sequences of various chemotherapy drugs increased it to18 months and now with new drugs such as monoclonal antibodies in the mix, this figure has increased to 2 years.
Early detection and treatment greatly increase the chances for successful outcomes for patients. But this is not always possible. Some patients present with colorectal cancer at an advanced stage, which is when some of the new drugs that are now available come into play. The most common site for colorectal cancer metastases is the liver, followed by the lungs and lymph nodes. However, it can spread to any part of the body.
This article takes a look at the recent progress that has been made in the treatment of advanced colorectal cancer, which is resulting in patients living longer with a better quality of life.
If the metastatic cancer is potentially resectable, then this should be the primary intervention to consider as this may lead to cure. This is particularly true if the cancer is in the liver only, but other isolated sites of involvement may be considered for surgery. Chemotherapy may also be considered, before and/or after such surgery.
The standard first-line treatment for inoperable metastatic colorectal cancer is combination chemotherapy and there are several options available.
The most commonly used first-line treatment in Australia is an intravenous infusion of the two chemotherapy agents, oxaliplatin and 5-fluorouracil (5-FU) or oxaliplatin with a tablet called capecitabine (Xeloda), respectively referred to as FOLFOX and XELOX.
These two treatment options are basically the same because capecitabine is converted into 5-FU within the tumour. The monoclonal antibody bevacizumab (Avastin), which slows down tumour angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A), may be given along with these two combinations.
First-line treatment regimes will vary according to the patient. For example, a patient may choose not to have chemotherapy or a frail patient may receive one chemotherapy drug instead of two.
“Many other decisions come into play with first-line therapy,” said Professor Chris Karapetis, a medical oncologist based at Flinders Medical Centre in Adelaide. “For instance, how long do you give the chemotherapy? Do you factor in breaks? Do you stop after a designated number of rounds or a designated duration of therapy? These are very much individualised decisions, there isn’t a clear gold standard approach.”
Basically it comes down to patient preferences, and how a particular patient is responding to the treatment. Some patients may choose to have a break and go on a holiday before returning to resume treatment. If first-line treatment is not working or is poorly tolerated, then stopping first-line and starting second-line treatment may be the next step.
“Ultimately the cancer will develop a resistance to first-line therapy,” Karapetis said. “And then you start thinking about second-line therapy.”
The most common second-line therapy for colorectal cancer in Australia is another chemotherapy drug, irinotecan (Campto), in combination with 5-FU — the FOLFIRI regimen. This may be given alone, in combination with a VEGF targeting monoclonal antibody (not supported by the PBS) or in combination with cetuximab (for KRAS wild-type cancer only).
Cetuximab (Erbitux ®) is the only monoclonal antibody available on the PBS for second-line use and can be added to this regimen. Cetuximab inhibits the epidermal growth factor receptor (EGFR) and can be offered as second or third-line treatment for patients with metastatic colorectal cancer in the Australian context — although this is dependent on the KRAS gene status in the cancer.
If a patient has a bowel cancer with a wild-type KRAS gene their doctor may prescribe cetuximab but if they have a mutation/s in their KRAS gene this treatment is not beneficial. Cetuximab is reimbursed in Australia only for patients who have a tumour with a KRAS wild-type gene.
In addition, cetuximab can be given alone or in combination with irinotecan, but in second line it is mostly given in combination.
Bevacizumab (Avastin) or aflibercept (Eylea), monoclonal antibodies that inhibits VEGF-A, can also be added. However, both aflibercept and bevacizumab are not available on the PBS but may be available to patients through an access program.
“Bevacizumab can be given through what is called ‘treatment across multiple lines’” explained Karapetis. “So a patient can effectively go from FOLFOX to FOLFIRI and keep the bevacizumab going through first- and second-line treatment.”
Continuing bevacizumab produces a longer response in patients and improves their overall survival. Eventually, the cancer finds a way around the second-line treatment.
“Patients inevitably develop secondary resistance — even if the cancer responds well initially, resistance develops, the cancer grows and then third-line treatment begins,” said Karapetis.
Once the cancer has evaded second-line treatment patients are given the option of going onto third-line treatment or managing with best supportive care.
Surgery is rarely an option at this stage because the potential for resecting metastatic colorectal cancer is limited.
Best supportive care was the standard third-line option for patients with chemotherapy refractory colon cancer until recently, when cetuximab (Erbitux ®) was developed. If a patient has not received cetuximab in second line, this may be an option for third line therapy.
“There is a real variation in practice in third-line treatment in Australia,” said Karapetis. “Probably about half of oncologists give cetuximab by itself and the other half give it with chemotherapy — no one really knows which approach is superior.”
The ICECREAM trial, a clinical trial co-ordinated by the Australasian Gastro-Intestinal Trials Group (AGITG), is currently comparing cetuximab alone versus cetuximab plus irinotecan to see whether the combination treatment is superior to cetuximab alone.
A successful trial
Cetuximab was developed in the US by ImClone Systems and proved to be active in early preclinical studies in cancer cell lines.
After what Karapetis described as “a colourful history” and what ImClone would call “a difficult path to market”, cetuximab was shown to be active in human trials and relatively safe for use in treating colorectal cancer along with several other cancers.
In Australia, the AGITG developed a clinical trial in collaboration with the National Cancer Institute of Canada to assess whether cetuximab improved outcomes for patients with metastatic colorectal cancer. These patients had been given all the known active chemotherapy drugs and their bowel cancer was now progressing.
“It wasn’t enough to say that cetuximab sometimes made a tumour shrink,” explained Karapetis, who was Principal Investigator for the trial. “And there was no good evidence to show that it helped people live longer or feel better. It also usually caused an acne-like rash. We needed evidence of a greater benefit than that, so we set up the C0-17 trial.”
The C0-17 trial was conducted across Australia, New Zealand and Canada. It included over 500 patients who were randomised to receive cetuximab alone or best supportive care.
“Cetuximab improved the survival of patients, but the magnitude of benefit was arguable modest in the overall population,” said Karapetis of the trial’s successful outcome. “Patients who received cetuximab also had a better quality of life with fewer symptoms and fewer admissions into hospital with complications.”
Digging deeper into the data
At the time the C0-17 trial was producing its results, other data was emerging about the role of the KRAS gene — cetuximab did not appear to be as effective in patients whose tumours had a mutation in the KRAS gene.
Tumour samples were obtained and a genetic test conducted from about 70% of the patients who participated in the C0-17 study. It turned out that about 60% of patients had a wild-type KRAS gene and 40% had a mutated KRAS gene.
A more careful analysis of the results for the C0-17 trial revealed that in patients who were treated with cetuximab, the wild-type KRAS gene was a positive predictor of benefit. Patients with KRAS wild-type gene who received best supportive care alone had a median survival time of about 4.5 months, whereas those who received cetuximab had a median survival of about 9 months.
“With the doubling of that median survival figure, this became much more clinically significant and meaningful,” reflected Karapetis.
In contrast, patients who had tumours carrying mutations in the KRAS gene received no benefit from taking cetuximab. And for patients who only received best supportive care, there was no difference in survival rates according to whether they had KRAS wild-type or mutant gene.
“We could then say with confidence that there would be no point giving cetuximab to a patient who has a tumour with a KRAS mutation,” Karapetis said. “This would exclude that group of patients from unnecessary therapy that has side effects, is expensive and would provide no benefit.”
The current treatment option for patients with KRAS mutations who have been through the chemotherapy treatments is best supportive care. Although Karapetis said regorafinib, a kinase inhibitor that has anti-angiogenic activity, provides a modest improvement in survival in patients with KRAS-mutant and KRAS-wild-type tumours.
Regorafinib is not on listed the PBS (the US FDA approved it for use in September 2012).
Another first-line treatment option?
The KRAS test has now become part of standard practice. In Australia, cetuximab can be used as a second- or third-line treatment.
In parts of Europe — Germany, France and Italy — cetuximab and chemotherapy are now commonly used as a first-line treatment for patients with KRAS wild-type advanced colorectal cancer.
“Data from several clinical trials shows that giving cetuximab in combination with chemotherapy versus chemotherapy alone as a first-line treatment does show a benefit, and recently we have seen data comparing cetuximab and chemotherapy with bevacizumab and chemotherapy in first-line treatment,” said Karapetis. The patients in the cetuximab group showed a survival advantage of almost 4 months. This trial used FOLFIRI as the chemotherapy backbone, and did not demonstrate a progression free survival benefit. Other trial results comparing cetuximab with bevacizumab are awaited.
Currently, bevacizumab and chemotherapy is the most commonly applied first-line therapy in Australia and there are PBS restrictions on the funding of cetuximab — it is only funded in second- or third-line treatment. However, cetuximab is registered for use in Australia in first-line and an access program is available.
The genetic test
In Australia, if a patient is going to be given cetuximab they must have a genetic test to determine the KRAS status of their tumour.
A tumour sample is needed for the test to be conducted, which, since it does not need to be fresh, can usually be sourced from the original tumour biopsy taken to establish a patient’s diagnosis.
A convenient online platform that clinicians can use to organise this genetic test is Merck Serono’s TestTailorTreat site. Specific information about a particular patient can be added to the site, including details about a patient and their pathology specimen details. According to Karapetis, the TestTailorTreat platform lists most, if not all, labs that conduct KRAS testing. Clinicians can nominate the particular lab they would like the pathology to be performed at.
“There are trials that I am involved in that require their own reference lab’s KRAS testing,” said Karapetis. “That’s the only time I wouldn’t use the TestTailorTreat site — it’s simple, effective and convenient.”
The genetic test is a PCR-based technique that screens for KRAS mutations.
Open to recruitment
The ICECREAM trial is looking at this panel of genes that Karapetis referred to as a “royal flush or full house”. This trial only includes patients with tumours containing the KRAS, BRAF, NRAS and PIK3ca genes in their wild-type form or a subgroup of patients with a particular mutation called the G13D KRAS mutation.
The combined analysis of data from patients involved in trials with cetuximab from Italy, Belgium, the Netherlands and Australia indicates that this G13D subgroup may gain some survival advantage from taking cetuximab. Although Karapetis pointed out that a similar analysis of trials involving panitumumab, another monoclonal antibody that inhibits EGRF, found that the G13D subgroup did not benefit from panitumumab.
“We think panitumumab and cetuximab are very similar, so the results are considered to be conflicting,” he explained, saying that more research needs to be done.
The ICECREAM trial is currently up and running with patients entering the trial and pathology testing for the gene is being conducted through the University of Melbourne.
Karapetis said there are some new drugs in development for colorectal cancer, mainly molecular-targeted therapies like the monoclonal antibodies or immune activators. Some are being tested in clinical trials, alone or in combination with chemotherapy, but their efficacy is not yet known.
The patient—clinician relationship
As a clinical researcher Karapetis said he is grateful for the contribution patients make to research and the courage they show in joining trials.
“These patients are taking risks, often not for their own personal benefit,” he said. “They are being randomised to treatment approach ‘A’ or treatment approach ‘B’ and are often not sure what they are going to be given. Sometimes they will be given drugs that are new, the full risks for which are not yet known.”
Clinical trials provide valuable information to prove that treatments are effective and thus guide the treatment of patients in the future. Trials are the only way that new treatments can be made available to patients.
Encouraging patients to join trials is an important role clinician’s play, for having enough participants in a study is key to its success. Discussing issues patients may have, such as the process involved in joining a trial and the need for informed consent or concerns they may have about being ‘guinea pigs’ is important.
“I also think it is important that patients know what we’ve found through experience in clinical trials,” Karapetis added. “Overall, despite the uncertainty patients may have, those who participate in clinical trials do have better outcomes.”
Evidence shows that patients who get involved in trials do have better outcomes. They are often a step ahead in terms of accessing the latest treatment, plus they receive close monitoring, care and support throughout the trial, as well as follow up support after the trial has been completed.
This knowledge can be used by clinicians to reassure patients that participating in a clinical trial will most likely give them a better outcome, through prolonging life and improving quality of life.
This story is published with thanks to sponsorship from Merck Serono.