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There is a lot of effort to find new drugs to treat cancer. When a new drug works well, we all cheer when it is approved and then use the new drug the same way in all patients. Then we move to the next new drug. But, should we stop there?
There is growing concern about overtreatment of some cancer patients. This may seem counterintuitive, considering cancer is a potentially deadly disease. However, there are several factors that may be contributing to overtreatment of cancer patients:
- Many drugs are approved for the largest populations of patients possible, even though some portion of the population may not benefit as much as other patients.
- We continue to find out more about the biology of cancer. For example, breast cancer is not one disease, but rather many. This means that one treatment may not fit all patients.
- Drugs are approved at one dose and duration. Once they are in use, it is challenging to re-evaluate their use in a lower dose or shorter duration.
- All cancer drugs cause harm (side effects) that can be debilitating and long lasting in those who live a long time after treatment.
This is just a partial list, but it outlines several reasons to reexamine how patients are treated based on the type, stage, and biology of their cancer. It is time to treat each patient as an individual instead of treating all patients the same. To illustrate the need to use cancer therapies in a way that benefits individual patients, groups are re-evaluating the treatment of HER2 positive breast cancer.
HER2 positive breast cancer
HER2 positive breast cancer is a subtype of breast cancer that is driven by the over expression of HER2 (human epidermal growth factor receptor 2). There have been great advances in the treatment of HER2 positive early stage breast cancer. People with early stage HER2 positive breast cancer have benefited from many new HER2 directed therapies including antibodies, antibodies with chemo attached, and small molecules. The very first studies of a revolutionary therapy tested an antibody (called trastuzumab (Herceptin®)) to HER2. The first studies of this drug used the dosing schedule of every three weeks for one year. Since then, it has been widely used to treat almost all HER2 positive breast cancer patients. Currently, the duration and use of HERCEPTIN® in early breast cancer is being reevaluated to make sure the right treatment is being used based on new knowledge about breast cancer subtypes, stage, and biology.
Shorter Duration – is less HERCEPTIN® better for some patients?
In early breast cancer patients, treatment with HERCEPTIN® was arbitrarily chosen to be every three weeks for one year. However, is this best for every patient? There have been many studies about the length of time HERCEPTIN® is given. For example, do patients who have a low risk of recurrence need an entire year of treatment or can a shorter time course be just as effective? Although HERCEPTIN® is well tolerated by patients, there are harms and costs associated with its use. One well known harm is heart damage, particularly when used with a common breast cancer chemotherapy drug, Adriamycin®. Also, infusion over one year adds extra time and cost for travel to a clinic to get the drug administered and the cost of the drug itself are added to a patient’s treatment.
Since HERCEPTIN® was approved, there have been several studies to test shorter treatment durations to find the right fit for the right patients, avoiding overtreatment. The following studies have looked at giving HERCEPTIN® for shorter duration in early breast cancer: short-HER (9-weeks vs 1-year), Fin-HER (9-weeks vs 1-year), SOLD (9-weeks vs 1-year), PERSEPHONE (6-months vs 1-year), PHARE (6-months vs 1-year) and HORG (6-months vs 1-year) (Chen, 2019 and Dieci, 2019). Even though Fin-HER showed a trend that 9-weeks may be a good alternative to 1-year in a group of patients at low risk of recurrence and PERSEPHONE showed 6-months may be a good alternative to 1-year, these results have not led to changes in clinical care. So, we still do not have a definitive option for shorter treatment times and still give HERCEPTIN® to all HER2 positive patients for one year.
One thing is very clear in these studies: the longer patients are on HERCEPTIN®, the greater the risk of suffering heart damage. Harms are important to avoid, and heart damage is one of the most feared in early stage breast cancer, where survivors live for a long time. Other burdens to patients are the time it takes to go to the clinic for infusions (every three weeks for one year) and the added cost of the drug. If patients can live just as long with a shorter treatment course, this could be an option for patients who are worried about the potential harms of an entire year of therapy.
Getting Treatment Right
We know cancer is many diseases and each comes with a different prognosis (how bad the cancer is). Some patients have a very good chance of surviving for a long time. Some will have a high risk of recurrence. Some will die from their cancer. Should we treat all these patients the same? All cancer drugs have side effects, many of which are irritating at best and life altering at worst. It is important not to overtreat patients who have a very good chance of surviving and surviving for a long time. Why is it so difficult to get cancer treatment right?
There are several challenges in conducting clinical trials to compare usual treatment with ‘less’ treatment. This is hard for patients to understand – that more may not be better. Many times, the harms from cancer treatment are either not talked about or not understood. It’s hard to understand and know how side effects will affect you every day and if they may continue for a long time.
A major challenge is in the type of trial that needs to be conducted. Typical trials test if a new drug is better (superior) to usual care. These are superiority trials, commonly used and well known to many. Superiority trials are not used when testing less treatment compared to usual care. To determine whether less treatment will be equal or less than usual care, a “non-inferiority” trial is usually conducted. Non-inferiority trials ask if a new treatment is not worse than another treatment by more than a specified “margin”. Deciding the ‘margin’, also called the threshold, is important. For example, if a margin of 10% is chosen, then the treatment can be worse than the usual treatment by up to 10% and still prove it is non-inferior to the usual treatment. This does not mean that it is equal to or the same as usual care. The margin is how much the patient is willing to give up in efficacy with this lesser treatment option. How much will you give up in efficacy to have a better quality of life and possibly avoid harms caused by usual care? This is why, even though PERSEPHONE showed 6-months of HERCEPTIN® was non-inferior to 1-year, practice is slow to change. Choosing a margin that is acceptable to both the clinician and patient is critical in order to change clinical practice. These studies are hard to conduct. Accrual can be challenging when offering less to patients and asking them if they are willing to give up a certain amount of efficacy.
Another challenge is patient selection. Looking at subgroups of patients have suggested the shorter course may be OK for patients with low-risk disease. However, looking at a smaller group in a large trial is not usually enough information to change practice (Fin-HER). Optimizing therapy to less treatment should be done with knowledge of the cancer subtype, stage and biology to select the patients who would most likely benefit from less treatment.
Treating each patient as an individual is coming. Treating all patients the same is on the way out. Precision treatment includes giving less therapy to some patients to optimize benefits while minimizing harms.
Edited by Rachel Cherney
Chen L, Zhou W, Hu X, Yi M, Ye C, Yao G. Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials. Cancer Treat Rev. 2019 May;75:12-19. doi: 10.1016/j.ctrv.2019.02.003. Epub 2019 Feb 28.
Dieci MV, Vernaci G, Guarneri V. Escalation and de-escalation in HER2 positive early breast cancer. Curr Opin Oncol. 2019 Jan;31(1):35-42. doi: 10.1097/CCO.0000000000000492.