The Controversy of Avastin

Background

Avastin is the commercial name for a drug called Bevacizumab (pronounced bev-a-siz-you-mab). It was first given approval in 2004 to be used alongside chemotherapy treatments for Colon (Bowel) Cancer. It has also been used in the treatment of certain lung, kidney, brain and breast cancers.

Roche, the company that make Avastin, received approval from the EU for treating ovarian cancers. The approval was for its use in combination with chemotherapy for first line treatment (December 2011) and first recurrence (October 2012).

The FDA, which is the approving body in the USA, have not been asked to approve Avastin for use with ovarian cancers because of a lack of evidence that it extends life, even though it can extend progression free periods by a few months, and also over concerns of some of the side effects. The FDA also withdrew approval for the use of Avastin in breast cancers in 2011.

The purpose of this post is to explain what Avastin is, how it works and how it is funded. However not everyone in the UK has equal access to this drug.

How does Avastin Work?
Unlike traditional chemotherapy drugs that prevent cell division Avastin is a biological therapy that interferes with processes in the cell. 

It works by stopping the growth of new blood vessels that are needed by the cancer cells for food and oxygen. 


Therefore the tumours starve and start to shrink as the cells die off. Doctors call treatments that interfere with the development of a blood supply anti angiogenesis treatments.




The drug is given through a drip into the vein and for ovarian cancer it is given every 3 weeks. 

Initially Avastin is given over 90 minutes, which is gradually reduced to 30 minutes if you do not have any problems with it.

Common Side Effects
More than 10 in every 100 people have one or more of these.

• High blood pressure occurs during treatment in about 1 in 4 people (25%) – this is monitored before every treatment and can be controlled with blood pressure tablets
• Feeling sick happens in about 2 out of 3 people (67%) but most people aren’t actually sick
• Diarrhoea and abdominal pain – this can be severe in up to 1 in 3 people treated (32%)
• Tiredness (fatigue) and weakness during and after treatment – most people find their energy levels start to improve when treatment ends
• Pain and weakness affecting your joints, muscles, chest and abdomen
• A drop in white blood cell count causing an increased risk of bacterial infection – infection may cause headaches, aching muscles, a cough, a sore throat, pain when passing urine, or may make you feel cold and shivery. Infections can sometimes be life threatening.
• Numbness or tingling in fingers and toes occurs in more than 1 in 10 people (10%) – this can cause difficulty with fiddly things such as doing up buttons. It may start within a few days or weeks and usually goes within a few months of finishing treatment
• Slow wound healing –  Avastin will not be started until at least 28 days after surgery or after any wounds have healed
• Poor appetite
• Constipation
• Watery eyes
• Difficulty speaking
• Nosebleeds

There are other side effects but these are less common and in some cases rare.

 
Avastin Trials for Ovarian Cancer (Source: Cancer Research UK)
The American GOG218 trial reported in June 2010 that Avastin with chemotherapy controlled advanced ovarian cancer for longer than chemotherapy alone. All the women in the trial had standard chemotherapy. Half of the women also had Avastin during the chemotherapy and then on its own once the chemotherapy had ended. Another large American trial reported in December 2011 and confirmed that adding Avastin to standard chemotherapy seems to control advanced ovarian cancer for about 4 months longer than chemotherapy alone.

In the UK a large, phase 3 trial called ICON 7 looked into whether adding bevacizumab to standard chemotherapy could lower the risk of ovarian cancer coming back after surgery. Between December 2006 and February 2009, 1528 women from Europe, Canada, Australia and New Zealand joined the trial. They all had ovarian cancer removed with surgery. Half the women had standard chemotherapy with carboplatin (Paraplatin) and paclitaxel (Taxol) every 3 weeks for 6 cycles of treatment and then no treatment until their cancer started to grow again. The other women had Avastin as well as the standard chemotherapy. When their chemotherapy finished they had 12 more doses of the Avastin every 3 weeks. 

 

The research team found that combining Avastin with standard chemotherapy lengthened the time before the cancer came back for some women. But it didn't help the women live longer. Overall, women who had Avastin and chemotherapy had an average of 2 months of extra time without the cancer coming back or growing. Women who had a more advanced stage cancer to start with had the most benefit. Women in both treatment groups had some side effects. The most common side effect of Avastin was high blood pressure but this was easily treated. 

The video above shows Dr Timothy Perren, from Leeds Teaching Hospitals NHS Trust being interviewed at European Society for Medical Oncology (ESMO) in 2010. At that time data for the overall survival (OS) figures from the ICON 7 trial were not available but were anticipated in 2012. The final results were presented at the European Society of Gynaecological Oncology (ESGO) meeting in 2013 . The data showed that women at highest risk of their cancer recurring lived on average 9.4 months longer than those who received chemotherapy alone.

Results of the ICON7, phase III clinical trial. Results of the ICON7, phase III clinical trial. ecancer.tv - Essential viewing for oncologists
The mEOC trial is comparing 2 different chemotherapy combinations with or without Avastin for a rare sub type of ovarian cancer called mucinous ovarian cancer. The doctors in this trial want to find out which chemotherapy combination works better to control cancer growth. And they want to find out whether adding Avastin to chemotherapy is a useful treatment for this group of women. Recruitment for the trial closed in August 2013 but the results have not yet been made public.

NICE Guidelines
NICE stands for The National Institute for Health and Care Excellence and it decides which drugs and treatments are available on the NHS in England and Wales and produces guidelines for medical professionals. 

The All Wales Medicines Strategy Group also makes some decisions for the NHS in Wales. Generally they follow NICE decisions. 

Scotland and Northern Ireland have separate organisations to make decisions.

The government developed NICE in 1999 to get rid of the post code lottery, which meant that some drugs and treatments were available in some parts of the country, but not in others. However with regards to access to Avastin this aim only appears to have been achieved to a certain extent in England.

Avastin has not been approved by NICE or the Scottish Medicines Consortium (SMC) as a first treatment or for first recurrence within the NHS on the grounds that it is not cost effective and does not increase overall survival. Although th latest data from the ICON 7 trial demonstrated that on average 9.4 months was added to the overall survival of patients most at risk. It is likely that this figure may increase as time goes by and is anticipated to reach the 12 months additional survival required by NICE.

In England only, doctors may be able to access this drug through the cancer drugs fund. 

The Cancer Drugs Fund (CDF)
The Cancer Drugs Fund is money the Government has set aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS in England. This may be because the drugs haven’t been looked at yet or because NICE have said that they don’t work well enough or are not cost effective. The aim of the fund is to make it easier for people to get as much treatment as possible. 
The Cancer Drugs Fund has been in operation since October 2010 and in April 2013 the management of the fund was taken over by NHS England. Now there is one national list of approved fast-track drugs which the Cancer Drugs Fund will routinely fund, giving uniform access to treatments across England.

Originally the Cancer Drugs Fund was only set to run until the end of March 2014 but this has now been extended until 2016. However the long term future of the fund is at present uncertain.

Avastin is approved for funding by the Cancer Drugs Fund in the following circumstances:

First-line treatment: Women with a new diagnosis of ovarian cancer can apply for funding for Avastin if they meet the following criteria:

• This is their first treatment for ovarian cancer
• They have stage III ovarian cancer, have undergone a debulking surgery but still have 1cm or more of cancer remaining. Or, they have stage IV ovarian cancer.

Second-line treatment: Women who have been told they have recurrent ovarian cancer for the first-time can access Avastin if they meet the following criteria:

• This is their first recurrence
• They have not previously been treated with Avastin
• They are platinum sensitive i.e. they finished carboplatin + taxol chemotherapy 6 months ago or more

Avastin is to be given in combination with two drugs, carboplatin and gemcitabine

Situation in Wales, Scotland and Northern Ireland
The governments of Scotland, Wales and Northern Ireland decide on how they spend money on health and so far have decided not to have a Cancer Drugs Fund or similar programme.

Therefore it is down to individual health authorities as to whether the drug is funded or not so where you live can determine what cancer treatments are available. 

This has become such an issue in Wales that women with ovarian cancer are crossing over the borders to register an address in England so that they can legally access the Cancer Drugs Fund. A recent article published by the Sunday Express explains the issues faced by patients:

 The good fight: A drug that can add years to lives of ovarian cancer patients

My own experiences of Avastin

As I was diagnosed and treated for first line before Avastin was given EU approval I was unable to access Avastin until my recent first recurrence.

I met with my oncologist in November 2013 following a CT scan that showed my cancer had spread to discuss my treatment options. The options included chemotherapy and hormonal treatments and I was told that this would be the last time that I would be allowed to have Avastin.

My consultant explained that whilst the chemotherapy may or may not work because of my low grade cancer that low grade cancers have responded to Avastin and this has been suggested by a retrospective review undertaken at Memorial Sloan-Kettering Cancer Center, New York by Dr. Aghajanian and her colleagues. I was also advised to start treatment straight away because of the cancer on my bowel. 

Getting the Avastin was a lot easier than I thought it would be and I started treatment the following week. The first treatment of Avastin was given over 90 mins and initially it made me feel sick and I also had a banging headache for which I was given some paracetamol. 

I was warned that I might get nose bleeds and whilst there may have been some spotting of blood the main impact of my nose seemed to be blocked sinuses and a runny nose. The inside of my nose also felt really irritated and this would happen every time I had the Avastin. Many of these symptoms have now settled down.

At first my blood pressure and urine samples were fine but gradually my blood pressure began to increase as did the protein in my urine. I am now on tablets to manage my blood pressure and my medication is reviewed on a regular basis by my GP.

I had a CT scan in February 2014 which showed a partial response including some minor shrinkage and no new disease. I had never had shrinkage before on carboplatin. At this stage with the recommendation from my consultant I decided to stop chemotherapy but continue with the Avastin. My CA125 has been falling gradually and we should have a better idea if the Avastin is still working when I have my next scan in May 2014.