Before you get too excited about the next sensationalized media headline or drug advertisement proclaiming a new “practice changing breakthrough” in cancer treatment, read this.
Almost weekly, there seems to be yet another announcement of a new and exciting cancer treatment that significantly improves outcomes compared with the current standard of care. Although, this occasionally is true, most of the time this boils down to very small actual benefits. Here’s what you need to ask your oncologist about before you get too excited about these frequently overhyped results.
- Find out the “ABSOLUTE” difference in outcomes and side effects between this new treatment and the other treatment it was tested against.
Most of the time, the media, drug companies and even your physician will tell you that a particular treatment ‘X’ reduces the risk of cancer recurrence (or other outcomes) compared with treatment ‘Y’ by a certain amount. When these results sound too good to be true, they often are. Here’s how.
You may hear the following from your oncologist: “By doing new treatment ‘X’ you will reduce your risk of cancer coming back by 50% compared with doing treatment ‘Y.'” That sounds very compelling, doesn’t it? But, before you get too excited, you need to find out if this is a “RELATIVE” or “ABSOLUTE” difference. I can’t stress enough how important this is for you to understand.
A RELATIVE difference is what is most often reported, but you actually want to know the ABSOLUTE difference.
A RELATIVE difference is the percentage difference between two outcomes (examples of a 50% relative difference):
- Treatment ‘X’ is better than treatment ‘Y’ by 50%
- Treatment ‘X’ reduces cancer recurrence by 50% compared with treatment ‘Y’
- Treatment ‘X’ improves survival by 50% compared with treatment ‘Y’
- Treatment ‘X’ has a 50% lower risk of side effects compared with treatment ‘Y’
Who wouldn’t be be interested in treatment ‘X’ when you hear results like these? 50% is a big difference, right? It might not be so impressive when you find out the ABSOLUTE difference.
An ABSOLUTE difference is the actual difference in outcomes, not a percentage. Here are examples in which the RELATIVE difference is 50% but the ABSOLUTE difference is much less impressive:
- Cancer recurrence rates are 1% with treatment ‘X’ and 1.5% with treatment ‘Y’ (absolute difference is 0.5%; a 50% higher relative recurrence risk with treatment ‘Y’)
- Survival rates are 5% with treatment ‘X’ and 2.5% with treatment ‘Y’ (absolute difference is 2.5%; a 50% lower relative survival rate with treatment ‘Y’)
- Side effects occur 10% of the time with treatment ‘X’ and 5% with treatment ‘Y’ (absolute difference is 5%; a 50% lower relative risk of side effects with treatment ‘Y’)
To calculate ABSOLUTE DIFFERENCES:
- Simply subtract the two risks
- If the risk of recurrence with treatment X is 2 out of 100 patients (2%) and treatment Y is 1 out of 100 patients (1%), the absolute difference is 2% minus 1% = 1% absolute difference
To calculate RELATIVE DIFFERENCES:
- Simply divide the two risks (examples of relative differences: relative risk, relative rate, rate ratios and odds ratios)
- Example: Risk of recurrence with treatment X = 1% and treatment Y = 2%. The relative difference is 1% divided by 2% = 50% relative difference. This would often be reported as ‘treatment Y reduces the risk of recurrence by 50% compared with treatment X.’ Clearly, this sounds more dramatic than the absolute difference of only 1%.
The most confusing issue we often face is when all that is reported is an ISOLATED RELATIVE DIFFERENCE. This is where a study or news article makes a claim that a treatment provides a “50% lower recurrence rate” or “10% better survival rate” compared with another treatment but gives no information about the actual numbers. As shown in the table below, there is a wide range of risks that can be reduced by 50%. Make sure to look for the actual data for each treatment group so you can make better sense of the absolute difference.
Once you find out what the ABSOLUTE difference is between treatment outcomes and side effects (and cost), you will be more educated to make an informed decision on your therapeutic options. Don’t accept a treatment unless you know this information.
Here are some real world examples:
Breast cancer chemotherapy for patients (stages 1-3):
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- No chemotherapy: 35.8% risk of dying from breast cancer at 10 years
- Chemotherapy (with Adriamycin): 29.3% risk of dying from breast cancer at 10 years
- RELATIVE difference: 35.8% divided by 29.3% = 22.2% improvement in breast cancer survival with chemotherapy
- ABSOLUTE difference: 35.8% minus 29.3% = 6.5% improvement in breast cancer survival with chemotherapy (The question you need to ask yourself is ‘would you accept a potentially toxic treatment with only a 6.5% absolute improvement in survival?’ Only you can answer that question.)
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- Chemotherapy (with Cytoxan, Methotrexate, Fluorouracil): 32.5% risk of dying from breast cancer at 10 years
- Chemotherapy (with Adriamycin and Cytoxan): 31.6% risk of dying from breast cancer at 10 years
- RELATIVE difference: 32.5% divided by 31.6% = 2.8% improvement in breast cancer survival with Adriamycin and Cytoxan chemotherapy compared with Cytoxan, Methotrexate, Fluorouracil
- ABSOLUTE difference: 32.5% minus 31.6% = 0.9% improvement in breast cancer survival with Adriamycin and Cytoxan chemotherapy compared with Cytoxan, Methotrexate, Fluorouracil (Patients who receive Adriamycin and Cytoxan have a higher risk of heart toxicity than those who receive Cytoxan, Methotrexate, Fluorouracil. Furthermore, Adriamycin causes hairloss. Question: Would you accept a drug regimen with a higher risk of heart injury and being bald if you knew that there was only a 0.9% absolute improvement in survival compared with the less toxic regimen?)
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Breast cancer (stages 1-3) chemotherapy Adriamycin+Cytoxan (AC) versus Taxol+Cytoxan (TC):
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- Breast cancer survival at 5 years with TC chemotherapy is 90% versus 87% with AC chemotherapy.
- The RELATIVE difference is: 90% divided by 87% = 3.4% better survival rate with TC
- The ABSOLUTE difference is: 90% minus 87% = 3% better survival rate with TC
- AC has a higher risk of cardiac toxicity than TC.
- TC has a higher risk of peripheral neuropathy than AC
- Based on these risks and the potential benefits of one regimen over the other, you and your oncologist will need to weigh the pros and cons to decide which regimen makes the most sense for you.
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- Breast cancer survival at 5 years with AC chemotherapy is 85% versus 85% with AC+PTX chemotherapy.
- The RELATIVE and ABSOLUTE differences are both 0%
- AC+PTX has a higher risk of neuropathic toxicity (peripheral neuropathy) than AC alone, so you have to ask your oncologist why they are recommending AC+PTX. Make sure to ask them what the absolute difference is in your situation before you agree to this treatment regimen.
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Breast cancer (estrogen receptor positive, lymph node negative) with Tamoxifen versus placebo:
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- Patients who took Tamoxifen for 5 years had an 80% overall survival rate at 10 years compared with 76% for those who took a placebo.
- Taking 5 years of Tamoxifen reduces the risk of death at 10 years by 5% (RELATIVE risk reduction) and 4% (ABSOLUTE risk reduction.)
- Taking Tamoxifen is associated with an increased risk of blood clots and uterine cancer, and side effects (i.e. hot flashes, etc.) Only you can decide if a 4% ABSOLUTE improvement in survival is worth it to you.
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- The risk of dying from breast cancer at 10 years in those who took an Aromatase Inhibitor (i.e. Anastrozole, Letrozole, Exemestane, etc.) for 5 years was 12.1% versus 14.2% with Tamoxifen
- The RELATIVE risk of dying from breast cancer at 10 years was 15% less in those who took an Aromatase Inhibitor for 5 years versus those who took 5 years of Tamoxifen; 12.1% divided by 14.2%
- The ABSOLUTE risk of dying from breast cancer at 10 years was 2.1% less in those who took an Aromatase Inhibitor for 5 years versus those who took 5 years of Tamoxifen; 14.2% minus 12.1%
- Both Tamoxifen and Aromatase Inhibitors have side effects and risks, so you would need to ask about these risks to decide which makes most sense for you.
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Breast Cancer Oncotype DX Breast Cancer Assay (“High Risk” Recurrence Score)
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- Oncotype DX is a breast cancer assay that helps to predict chemotherapy benefit and the likelihood of distant breast cancer recurrence for patients with invasive breast cancer. Here is an example report from a patient who has a “high risk” recurrence score (38):
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- Based on her “high-risk” recurrence score (38), this patient would be counseled that her risk of developing a distant breast cancer recurrence (metastatic disease) in 10 years is 50% less if she chooses chemotherapy + 5 years of Tamoxifen versus taking 5 years of Tamoxifen alone (a 50% RELATIVE difference.) That sounds like a huge benefit for the addition of chemotherapy, right? Maybe not.
- I think a much more useful statistic for her is the ABSOLUTE difference, which is only 10% (20% minus 10%)
- Although a 10% ABSOLUTE benefit is nothing to sneeze at, it may not be enough of a benefit for some patients to accept the possible toxicities of chemotherapy.
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Lung cancer chemotherapy for patients with stage 4 disease:
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- Chemotherapy reduces the risk of dying from lung cancer by 27% (relative risk) and 10% (absolute risk) compared with those not treated with chemotherapy
- This small absolute improvement in the risk of dying from lung cancer at 1 year with chemotherapy equates to a 1.5 month improvement in survival compared with those who do not get chemotherapy
- A 1.5 month ABSOLUTE difference in survival may or may not be worth the toxicity of treatment. That is something you need to discuss with your family and your oncologist.
- Caveat: some patients with non-small cell lung cancer will have genetic mutations (i.e. EGFR, ALK, HER-2, BRAF, etc.) for which there are newer, targeted drugs that can yield a much greater response to treatment than standard chemotherapy. Even if you have one of these cancers, you still want to ask about the absolute benefit in outcomes. New immunotherapies (i.e. immune checkpoint antibodies: anti-PD-1, PD-L1 and anti-CTLA-4 agents) may also be an option for you, but ask about the absolute benefits and risks.
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Other Issues Besides Cancer Outcomes:
Quality of life:
Even though treatment ‘X’ may not be very superior to treatment ‘Y’ in terms of survival outcomes, it may offer a significant improvement in quality of life symptoms (i.e. pain, shortness of breath, neurologic symptoms, etc.) Alternatively, certain treatments are more toxic than others. Both of these issues must also be weighed in the decision of choosing treatments. You will need to discuss these with your oncologist to determine if a treatment makes sense for you.
Treatment cost:
Cancer treatments are often expensive. If there is little difference between the two treatment regimens in terms of efficacy, quality of life improvements and toxicity, then cost could be an important factor to weigh in your decision on the treatment of choice.
The Bottomline:
Ask your oncologist to discuss the ABSOLUTE differences between treatments (or even doing no treatment), especially if the risks are higher with their recommended treatment.
