What are the treatments for bowel cancer?
The most important treatment for cancer of the bowel (“colon cancer”) is an operation to remove it, along with part of the bowel. In fact, for many patients this operation completely cures the cancer. However unfortunately, in some patients, tiny cancer deposits, too small to see or detect, can be left behind at the time of the operation; these then develop into a recurrence of the cancer months or years later. Research over the past decades has shown that a course of drug treatment given after the operation helps to reduce the risk of cancer recurrence. This treatment is called adjuvant chemotherapy, and it is recommended for most patients if they are at risk of a recurrence after bowel cancer surgery.
What is the FOxTROT study?
Although it certainly helps, adjuvant chemotherapy does not eliminate the risk of cancer recurrence and so research continues to find ways of further improving treatment. FOxTROT is a research study testing two new types of treatment to see if these are better than standard treatment: The first is to give some of the chemotherapy before the operation (“preoperative chemotherapy”) with the aim of shrinking and controlling the cancer as soon as possible. The reason for this is that before surgery any cancer deposits are likely to be smaller, and perhaps easier to eradicate, than if we wait until after surgery. Drug treatment before the operation may also reduce the size of the tumour, making it easier for the surgeon to completely remove it. The second treatment being tested is a new drug called "panitumumab". This is an “antibody” treatment designed to bind directly to cancer cells and stop their growth. Panitumumab, used on its own, has been shown to be relatively safe and is effective in helping control bowel cancer that has spread. We are trying to find out in FOxTROT whether giving panitumumab along with chemotherapy also helps people with less advanced disease whose cancer can be treated by surgery.
Why am I being invited to take part in FOxTROT?
Your specialist will have invited you to consider taking part in FOxTROT because you have a form of bowel cancer that requires an operation, and for which adjuvant chemotherapy is likely to be helpful. All patients like you are being invited to take part to see when the best time is to give chemotherapy and whether the new drug panitumumab helps with chemotherapy. The FOxTROT study aims to include over 1000 people with colon cancer from dozens of hospitals throughout the UK and elsewhere.
Do I have to take part?
No. Taking part in research is always voluntary. If you decide to take part you will be given this information sheet to keep, and will be asked to sign a consent form, but you are still free to withdraw at any time and without giving a reason. If you decide not to take part, then you don't have to give a reason why and no-one will think badly of you for not wishing to take part. Your specialist will be happy to talk through alternative options, for example the standard treatment of surgery followed by adjuvant chemotherapy.
What does the standard treatment involve?
The standard treatment starts with an operation to remove the part of the bowel containing the cancer. There are several different types of bowel operation, depending on the exact position of the cancer and various other factors, and your surgeon will discuss with you in detail which is best in your case. After surgery, patients spend about a week in hospital, then need a period at home to fully recover from the effects of surgery. This varies from patient to patient, but usually takes between 4 and 8 weeks. Following this, patients at risk of recurrence often receive a course of adjuvant chemotherapy. There are several different types of adjuvant chemotherapy available, usually involving about 6 months of treatment with a combination of two or three drugs. Again, your oncologist (cancer specialist) will discuss with you in detail which type of chemotherapy is best in your case.
What are the FOxTROT study treatments?
If you decide to take part in FOxTROT, you would receive one of four treatments:
A) Oxaliplatin and fluoropyrimidine (OxFP) chemotherapy for 6 weeks before surgery (pre-operative chemotherapy) and then for 18 weeks after surgery
B) The same 6-week course of pre-operative OxFP chemotherapy but with panitumumab added followed by surgery and then 18 weeks of post-operative OxFP chemotherapy
C) Standard treatment (i.e. a 24-week course of post-operative OxFP chemotherapy)
When the study is complete, we will compare the effectiveness and side-effects of treatment in patients who received each of these treatments. This will include looking at the results of surgery, whether cancer recurrence occurred, and assessing any unwanted side-effects of each treatment. We will also see whether different types of cancer or patients with different genetic or other characteristics have a different reaction to the treatments.
Which of these treatments would I receive?
Neither you nor your doctor can choose which treatment you receive. The decision as to which treatment group people are allocated to is made by the FOxTROT study office randomly (like a lottery draw). This is essential so that a fair comparison can be made between the different treatment groups. Dividing people into treatment groups in this way is what is called a 'randomised clinical trial' and it is the standard and most reliable way of comparing different treatments. However, FOxTROT is not a 'placebo' trial; there are no “dummy treatments”, all patients will be treated with the most effective available chemotherapy, which we know will help reduce the chance of the cancer coming back, and both you and your doctors will know which treatment you are receiving.
What exactly does the FOxTROT chemotherapy involve?
In FOxTROT, doctors can choose either one of two similar types of OxFP chemotherapy:
1) A drug combination called “OxMdG” This is a standard chemotherapy that has been tried and tested in many thousands of patients. We know that it is one of the most effective treatments for colon cancer and it is one of the types of chemotherapy recommended by the National Institute for Clinical Excellence (NICE). The OxMdG treatment starts with two chemotherapy drugs, called oxaliplatin and folinic acid, given as a “drip” into a vein over two hours. After that, another drug called fluorouracil is given very slowly into the vein, over the next 46 hours. This 48-hour treatment is given twelve times at 2-week intervals amounting to 24 weeks of treatment in all. There are several different methods of giving OxMdG and your doctor or nurse will discuss with you the way that suits you best. Most commonly it is given at home, using a small portable pump. To receive OxMdG chemotherapy, you will need to have a thin flexible tube fitted in either your arm or your chest. This leads into one of your veins, and chemotherapy is given through it. Once fitted, it avoids many needles, and can stay in for the duration of your treatment.
2) A drug combination called “OxCap” Again, this is a standard chemotherapy known to be one of the most effective treatments for colon cancer that has been tried and tested in many previous patients. The two drugs used are oxaliplatin and a drug that acts in a similar way to fluorouracil and folinic acid called capecitabine. Oxaliplatin is given as a “drip” into a vein over two hours and capecitabine is a pill taken twice daily for two weeks afterwards. Eight courses of OxCap are given at 3-week intervals, again amounting to 24 weeks of treatment in total.
Your doctor will discuss with you, before starting any treatment, which of these two treatments is to be recommended in your case, and what it involves.
How long does treatment go on?
A third of the patients who take part in FOxTROT receive standard Post-operative Chemotherapy. That is to say, there is a 1 in 3 chance that if you decide to participate in FOxTROT you will have an operation first, then a period of recuperation, then a 24-week course of adjuvant chemotherapy, as described above. The operation will usually take place 1-3 weeks after entry into the study, followed by a 4-8 week recuperation period after surgery, and then 24 weeks of adjuvant chemotherapy. So, the full course of treatment is normally completed in 29 – 35 weeks.
The remaining two thirds of patients in FOxTROT receive Pre-operative Chemotherapy. This treatment starts before the operation, and involves giving the first 6 weeks of chemotherapy (either three 2-week courses of OxMdG or two 3-week courses of OxCap) before surgery with the remaining 18 weeks of chemotherapy given after surgery. The 6-week course of pre-operative chemotherapy would normally start about a week after entry into FOxTROT, and would be followed by a rest period of 3-4 weeks, to allow the treatment to have its full effect and for any side effects to settle, then the operation, a 4-8 week recuperation period after surgery, and then the remaining 18 weeks of adjuvant chemotherapy. So, the full course of treatment is normally completed in 32 – 37 weeks.
Half of patients in the pre-operative chemotherapy group receive, in addition, panitumumab treatment for the first six weeks of chemotherapy. This will entail an additional drip of about 1 hour, given through a vein, before the start of each course of chemotherapy (i.e. three injections at 2-weekly intervals if receiving OxMdG). Taking panitumumab should not make any difference to the total length of treatment.
What risks are there from these treatments?
Whether or not you take part in the FOxTROT study, the recommended treatment for your condition would involve surgery and a course of adjuvant chemotherapy. There are small risks from any form of major surgery and chemotherapy can also produce unwanted effects. Your doctor will explain in detail what these treatments involve. Some patients get no side-effects, but it is helpful to be forewarned of some of the things that could possibly happen with OxMdG or OxCap chemotherapy:
For a few hours or days after starting treatment, you may feel tingling ('pins and needles') in the hands and feet if you touch cold things or go out in the cold. You may also feel tingling in the throat. This is harmless and will settle without treatment.
Just occasionally, people can become allergic to one of the drugs, though this is rare. If, while the drip is running, you develop a racing heart beat, an itchy rash, wheezing or a swollen tongue, please tell the nurses immediately.
Chemotherapy can cause diarrhoea. You will be given anti-diarrhoea tablets to use if this is mild, but if you have severe diarrhoea (more than 4 watery stools in a day) please telephone the hospital for advice.
Some patients find they feel a little sick for a few days after starting treatment, but vomiting is unusual. You will be provided with some anti-sickness tablets to take if you start feeling sick. If you vomit more than once in a 24-hour period, please telephone the hospital for advice.
Some people notice soreness in the mouth or a change in taste for some foods. You will be provided with a mouthwash which may help. If you develop ulcers or pain in the mouth, please telephone the hospital for advice.
Some people feel more tired than usual during chemotherapy treatment. There is no easy answer to this, but if you are affected you may find it helps to set aside a rest period in the middle of each day.
Any chemotherapy treatment may temporarily reduce your resistance to infections, so if you develop a high temperature or other symptoms of infection between treatments, you may need to come to the hospital for an urgent check-up.
Occasionally, we meet someone who is particularly sensitive to the effects of chemotherapy and has more severe side-effects than expected. If that happens, treatment is stopped until the problems have settled; it is usually then possible to continue treatment at a lower dose.
Women of childbearing potential must: have a negative pregnancy test prior to trial entry and avoid pregnancy during and for 6 months after study treatment. Men with a partner of childbearing potential must use adequate, medically approved, contraceptive precautions during and for 90 days after the last dose of study treatment.
In FOxTROT some of the patients will receive the antibody treatment, panitumumab, in addition to chemotherapy. Some additional side-effects can be caused by panitumumab. Nearly all patients receiving antibody will develop a rash, which is usually mild. It can take the form of red blotches or spots, or may resemble acne. Occasionally it can become more severe with itching, blisters or flaking. Other skin side-effects from panitumumab may include swelling and soreness around your nails and at the tips of your fingers and toes. Some patients receiving antibody have reported loss of appetite, or feeling tired, dizzy, anxious or short of breath. It may cause your muscles and joints to ache or cause slight swelling in your hands and feet. Having antibody alongside chemotherapy may also increase the likelihood that you will experience diarrhoea after the chemotherapy. There is a very small chance that antibody treatment can cause a heart attack: this does not seem to be a problem with panitumumab, the antibody used in FOxTROT, but some patients treated with a similar drug have experienced heart damage. If you experience a racing heart beat, chest pain or any other symptom that you believe may be related to your heart, please contact the hospital immediately. As with any new drug, there is a potential that you may experience other side-effects not previously observed.
How will my condition be monitored?
Your progress will be monitored carefully. Before starting FOxTROT you will have had investigations to assess your cancer, including a CT scan, a colonoscopy test and blood tests. Before starting the study, your medical team will check your records and the results of your examinations and blood tests to make sure you are suitable for the study.
During chemotherapy, you will be asked about any side-effects you have experienced and will have a blood test at each treatment visit. If you are one of the two-thirds of patients receiving preoperative chemotherapy, you will be asked to have another CT scan after the treatment and before surgery, to assess your response to chemotherapy and how this might impact on the type of surgery you receive. A second scan is currently not standard practice for colon cancer patients although in other cancer types where preoperative chemotherapy is the standard of care - for example stomach, lung and oesophageal cancer - a post-chemotherapy pre-surgery CT scan is the routine clinical practice. This second scan is, however, optional and, if you do not wish to have this scan, it will not affect your participation in FOxTROT.
When you have your operation, you will of course be carefully monitored throughout the operative period. Your surgeon will send all removed tissues for examination in the hospital's pathology laboratory, and will discuss the result of the operation with you.
After the operation, and a period of recuperation, you will be assessed by the oncologist and, when sufficiently recovered, you will start your post-operative chemotherapy. You will be monitored throughout this time for any side-effects or other problems.
After completing the treatment, there will be a period of follow up, during which you will be asked to attend the clinic regularly for check ups, with occasional blood tests and scans to assess your progress.
What are the possible benefits from taking part in FOxTROT?
We are taking part in the FOxTROT study because we hope that pre-operative chemotherapy and/or panitumumab treatment may give better results than standard treatment. However we cannot be sure in advance whether this is the case – that is the reason for doing this study. The main benefit from FOxTROT will be that the information gained from the study will help improve the treatment of patients in a similar condition to yours in the future.
What are the possible disadvantages of taking part?
The majority of patients’ cancers are controlled (i.e. shrink or stop growing) during chemotherapy treatment. However, occasionally, cancers grow despite treatment. We cannot rule out the possibility that your cancer could grow during pre-operative treatment, in which case surgery could be less, rather than more, effective. This is why we are collecting blood samples to try and find out why some cancers are sensitive to chemotherapy and some are not. Also, while the chemotherapy and antibody treatment have been tried and tested in many patients, the majority did not go on to have surgery. It is possible that the complication rates of surgery could be increased by giving these treatments before surgery. It is standard practice to assess and monitor your cancer using CT scans (these take images of your body using x-rays). By taking part in the trial you may receive one CT scan more than for standard care and so will receive extra radiation. Any radiation is associated with an increased risk of developing cancer. However the risk associated with a single CT scan is very small (less than 1 in 1300) and negligible when compared with the 1 in 4 lifetime risk of cancer.
To protect patients' safety, an independent committee of cancer experts will review the results of the FOxTROT trial on an ongoing basis, as well as information from other relevant trials around the world. This is so that if the new treatments unexpectedly turn out to be worse than the standard, that would be detected as soon as possible and the trial stopped.
What if something goes wrong?
If you are harmed by taking part in this research project, there are no special compensation arrangements. But, whether or not you take part, you would retain the same legal rights as any other patient treated in the National Health Service. If you are harmed due to someone’s negligence, then you may have grounds for a legal action but you may have to pay for it. Regardless of this, if you wish to complain, or have any concerns about any aspect of the way you have been approached or treated during the course of this study, the normal National Health Service complaints mechanisms should be available to you.
Will my taking part be confidential?
If you decide to take part in FOxTROT, the information collected about you during the course of the trial will be kept strictly confidential in the same way as all of your other medical records. Information about your disease and progress will be sent by your doctors to the FOxTROT Study Office at the University of Birmingham Clinical Trials Unit (BCTU), on paper and electronically, where it will be securely stored under the provisions of the 1998 Data Protection Act and/or applicable laws and regulations. Your GP, and the other doctors involved in your clinical care, will be kept informed, but otherwise all information about you and your treatment will remain confidential.
If you take part in the study, your relevant medical records may be inspected by authorised individuals from the BCTU and by Cancer Research UK (who are funding the study). They may also be looked at by the regulatory authorities. The purpose of this is to check that the study is being carried out correctly. A pharmaceutical company, Amgen Inc, is providing antibody (panitumumab). At the end of the study, a copy of the trial data will be sent to Amgen or its subsidiary companies. It will not be possible to identify you from these data and it will be kept strictly confidential.
When the trial is complete the results will be published in a medical journal, but no individual patients will be identified. If you would like to obtain a copy of the published results, please ask your doctor.
You can decide not to continue with study treatment at any time but, if you do, we would still like to follow up your progress. An important aim of the study is to find out how many patients complete their treatment and how people get on if they withdraw from treatment. For this reason, your data and samples would remain on file and be included in the final study analysis. In line with Good Clinical Practice guidelines, at the end of the study, the data will need to be securely archived for a minimum of 15 years. Arrangements for confidential destruction will then be made. If you withdraw consent for your data to be used, it will be confidentially destroyed.
If you take part in FOxTROT, we would like to request your permission to take an extra blood sample and to send this along with some of the surplus material from your biopsy and from the specimen removed at surgery to a laboratory where some genetic tests will be done, for bowel cancer research. The research involves extracting DNA or other chemicals from the tumour to see whether it is possible to predict which patients will benefit most from each treatment. All such work is anonymous: your specimens will be identified by a code number, not your name, and neither you nor your relatives will be identified or contacted and the result will not be added to your medical records.
We need to test the biopsy sample for any other abnormalities of the KRAS gene for patients to be eligible for panitumumab. Otherwise, these studies will not affect your treatment in any way, and you are free to withhold this permission without affecting your participation in FOxTROT or your relationship with your doctor.
In some hospitals, patients taking part in FOxTROT may be invited to participate in an extra piece of research to obtain an additional biopsy sample of the tumour. Your doctor or nurse will talk to you about this if your hospital is participating.
Who has organised, reviewed and funded the research?
The FOxTROT study was developed by the National Cancer Research Institute's Colorectal Cancer Clinical Studies Group, and is funded by the medical charity, Cancer Research UK. The study also has the full support of the Bobby Moore Fund. The study is coordinated by the Clinical Trials Unit at the University of Birmingham. Amgen Inc is providing the panitumumab free-of-charge but is not involved in the design, running or analysis of the study. The research has been reviewed by all of these organisations, and also by the West Glasgow Multi-centre Research Ethics Committee.
What do I need to do if I decide to take part?
If you do decide to take part you will be asked to sign a consent form. If you want to think about it for longer, or discuss it with friends or relatives, then you can take this information sheet and the consent form away with you and sign, witness and return the form later. You will not need to make an extra visit to the hospital. Whether you agree to take part now or later, you would be free to withdraw at any time after and without giving a reason. All you would need to do is to contact your surgeon either in writing or by telephone and your name will be withdrawn from the study. This will not adversely affect the care that you receive.
If you have any further questions about your disease or clinical trials, please discuss them with your doctor. You may also find it helpful to contact MacMillan Cancer Support, an independent patient advisory group, by:
calling their freephone number 0808 808 00 00
89 Albert Embankment
The FOxTROT study coordinating centre is located at the Birmingham Clinical Trials Unit, Public Health Building, University of Birmingham, Edgbaston, Birmingham B15 2RTT.