Posts

19 December 2019

study recently published in the Journal of Clinical Oncology* found that the use of some vitamins and supplements before or during chemotherapy treatment for breast cancer was associated with increased recurrence and mortality rates.

Vitamins and supplements may interfere with or prevent the desired chemotherapy or radiation therapy effect of cell death, so it is common practice to advise patients to stop (or not to start) taking vitamins and supplements while undergoing treatment. The patients in this study were all undergoing chemotherapy for breast cancer, using the same medications, but with different dosing schedules. The treatment regimen was doxorubicin (also known as Adriamycin), cyclophosphamide and paclitaxel, commonly referred to as AC-T. Patients were surveyed on vitamin and supplement use prior to starting chemotherapy and after treatment. Median follow up was 8.1 years.

There were 1134 patients included in this study. 251 experienced a recurrence and 181 died – these patients were more likely to be older, Black, post-menopausal, have a higher body mass index, and have poorer tumor prognostic factors including 4 or more positive lymph nodes, and estrogen / progesterone receptor or Her2/neu negative tumors. 17.5% reported use of any antioxidant (vitamin A, vitamin C, Vitamin E, carotenoids, and co-enzyme Q12) during chemotherapy treatment and 44% used multivitamins.

The findings included:

  • Use of antioxidant supplements both before and during chemotherapy was associated with an increased risk of cancer recurrence and death, but the numbers were not statistically significant
  • The researchers were not able to determine if there was any specific relationship between the use of individual antioxidant supplements and risks of recurrence or death. There was a relationship with vitamin A but analysis for this supplement only included 5 patients
  • There were no relationships between use of antioxidants only before or only during treatment and outcomes
  • Vitamin B12 use both before and during chemotherapy was associated with increased risk of recurrence and death 
  • Iron use during chemotherapy was associated with higher recurrence risks as was use both before and during treatment 
  • Omega 3 use both before and during treatment was associated with increased recurrence risk but not death
  • There did not appear to be any association between recurrence or survival and the use of multivitamins, vitamin D, glucosamine, melatonin, acidophilus, folic acid, or vitamin B6

One of the authors’ conclusions was that “we found some support for the notion that use of dietary supplements during chemotherapy could have a negative impact on recurrence and overall survival.” It is important to stress that this was an observational study, which means direct cause and effect cannot be determined. Relative, not absolute risks, were reported. In addition, the number or women who reported taking non-multivitamin supplements was just under 200. While news reports noted that supplements were associated with a 40% increased risk of recurrence a weaker association with death, these numbers did not meet statistical significance. The authors noted that “a review… in 2010 concluded that insufficient evidence existed with regard to safety of dietary supplements to make recommendations, and that may still be the case.”

Despite the limitations of this study and the inability to draw firm conclusions, it is still recommended that patients who receive a recommendation for chemotherapy or radiation therapy inform their medical team of all vitamins and supplements that they are taking, and it still is considered best practice to avoid antioxidant supplements while undergoing treatment.

*If you are not able to access the full study and would like a copy, please email me: contact at drattai dot com

4 June 2018

The American Society of Clinical Oncology (ASCO) annual meeting, a gathering of over 40,000 oncology specialists, was held this past weekend in Chicago. One of the studies that received a significant amount of press attention was the TAILORx study.

There are several genomic tests which evaluate a tumor’s DNA to better determine how aggressive that tumor is, and how likely it is to recur without chemotherapy. The Oncotype Dx test was the first commercially available one. A sample of tumor is sent for analysis and the result is reported as a “score” which is then assigned to one of 3 categories – low, intermediate and high risk of recurrence. A sample of the report generated from the test is shown below. It is important to note that the Oncotype Dx test was validated in patients who received endocrine therapy, so the results assume treatment with tamoxifen or an aromatase inhibitor. It is appropriately used in patients with Stage I or II breast cancer, with spread to 1-3 underarm lymph nodes, if the tumors are estrogen receptor positive (ER+) and Her2/neu negative (Her2-). The results of the low risk cohort were published in 2015, which confirmed that patients with low scores receive little benefit from chemotherapy.

Sample Oncotype Dx Report

The study presented at ASCO reported on the results of the intermediate risk group. For the purposes of the study, intermediate risk was defined as a score of 11-26. It is important to note that in patients outside of the study, intermediate risk is a score of 18-31. However, as patients in the lowest risk category did not receive chemotherapy as part of this study, the categories were shifted to the left to be more cautious. Patients enrolled in the study were women between the ages of 18-75, with a median age of 55-58. Eligibility criteria included patients who had tumors smaller than 5 cm, ER+, Her2-, and with negative underarm lymph nodes (as determined by surgical pathology – all patients in this study underwent surgery). Patients with an Oncotype Dx score of 11-26 (69% of the total study population, about 6700 patients) were then randomized to chemotherapy followed by endocrine therapy, or endocrine therapy alone. Median follow up was 7.5 years.

The study showed that there was no significant difference in the overall survival (~94%), invasive cancer disease free survival (~84%) or distant disease free survival (~95%) between the 2 groups. However, in women under the age of 50, it was found that those with scores of 16-25 did receive some benefit from chemotherapy. It is unclear from the study if the benefit in these patients was specifically from the chemotherapy, or if it was that menstrual cycles and ovarian function are suppressed with chemotherapy, which then lowers estrogen levels. The authors raised the question of whether or not similar results in this group of patients could be achieved using medications to suppress the ovaries (which would induce menopause) and an aromatase inhibitor instead of chemotherapy.

It is important to note that a low risk score does not mean the patient will not develop a recurrence or metastatic disease – it simply means that the risk of recurrence is extremely low and that chemotherapy will not significantly improve on that low risk. It is also important to keep in mind that this study did not include patients with triple negative or Her2/neu positive breast cancer, or patients where the cancer had spread to the lymph nodes.

There are several commercially available genomic tests, and which test is used for a particular patient is often related to guideline recommendations and physician preference. Most of these tests are covered by insurance but the costs are high (~$4500.00) and patients should check with their insurance to determine if they have a share of cost. Most of the testing companies have payment assistance programs. For patients right on the edge of one of the risk categories, treatment decisions are not always as clear cut, and should be made in the context of the patient’s other disease factors and as part of a balanced discussion of the risks and benefits of treatment as well as patient preferences.

There has been a lot of focus on de-escalaton of therapy, and rightly so. While chemotherapy and other toxic treatments have their place, there are significant short term and long term side effects, so determining which patients have the best likelihood of benefit from these treatments is important. Not all cancers will respond to chemotherapy, and in those cases, the patient is subjected to all of the harms and receives none of the benefit.

Additional information from the ASCO Post 

25 August 2016

A study published today in the New England Journal of Medicine reports on the 5 year results of the MINDACT (Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy) trial. This study was designed to evaluate the use of a tumor gene signature test (MammaPrint) compared with standard factors to assess the need for chemotherapy.

This study enrolled 6693 women in 112 countries who had undergone surgery for Stage I and II breast cancer. Once patients were registered, they were stratified based on risk. Risk was assessed both by the MammaPrint (MP) score as well as standard clinical – pathological markers (CP) such as tumor size, grade, ER/PR status, and Her2/neu expression calculated using the Adjuvant! Online tool.

2745 patients who had low risk MP and CP scores did not receive chemotherapy; 5 year metastasis-free survival in this group was approximately 97.6%. These findings were consistent with those reported using a different genomic test, the Oncotype Dx test, which also demonstrated good results without chemotherapy in low risk patients. 1806 patients who were high risk by both assessments received chemotherapy and 5 year metastasis-free survival in this group was approximately 90.6%.

The other 2 groups were those with discordant results, and these patients were randomized to either chemotherapy / endocrine therapy or endocrine therapy. The results for the 592 patients with high risk MP scores but low risk CP assessment are pending. The recently published study focuses on the 1550 patients with low risk MP scores but were high risk based on CP assessment.

The study demonstrated that in these patients, chemotherapy provided a slight benefit: 1.5% improvement in survival without metastatic disease, 1.4% improvement in overall survival, and 2.8% improvement in disease free survival. The study was not powered or designed to determine if these differences were statistically significant.

On the surface, the study seems to indicate that chemotherapy is of little to no benefit for those patients with low risk MP scores and high risk CP features. There is no question that genomic tests such as the MammaPrint have revolutionized our treatment recommendations. We now have the ability to obtain more detailed information about an individual patient’s tumor biology, which can help us guide treatment decisions. It is clear that our traditional methods of assigning risk such as tumor size, grade, and node status, do not always tell the whole story, and it is no longer acceptable to recommend chemotherapy “just to be sure”. The use of genomic tests in appropriate patients is very important to avoid the real dangers of over treatment. But as this study was not designed to assess statistical significance (rather, “non inferiority“), can we say that the benefits demonstrated from chemotherapy may not be important for an individual patient?

Median follow up in this study was was 5 years. 48% of patients were lymph node positive, 93% had grade 2 or 3 disease, and 34% were age 50 or younger. These factors are more often associated with an earlier risk of recurrence, so 5 years may be sufficient to note a difference in survival rates. It was also stated by the authors that “adjuvant chemotherapy exerts most of its beneficial effects early in the course of the disease”. However, they also noted that many of the tumors were ER+, which may recur well past 5 years. 10 year follow up is planned.

In an accompanying editorial, Drs. Hudis and Dickler point out that “although we may all agree that a 1% risk of distant metastasis at 5 years on the basis of genomic testing eliminates any potential benefit of chemotherapy, at what point would we begin to have differing opinions and perhaps mixed results from clinical trials? Answering this question is even more challenging, given that all chemotherapy is not the same in terms of efficacy or toxicity and that patients and health care providers bring subjectivity and personal values to their treatment decisions.”

As was pointed out during a recent online exchange (by a woman who had a low recurrence score and now has metastatic disease), these tests are not guarantees. While the numbers are low, some women in the low risk group developed metastatic disease. It is not known if chemotherapy would have been of benefit, but it does demonstrate how percentages are applicable to populations, not necessarily to individuals. We do not yet have a test that will predict the outcome with 100% certainty. The test results should be presented as part of a discussion which includes the patient’s preferences, values and concerns – concerns regarding cancer recurrence as well as potential side effects of therapy.

29 September 2015

One of the most common questions asked by a newly diagnosed cancer patient is “Will I need chemotherapy?”. Almost everyone is aware of the toxicity related to chemotherapy, and the fact that it is a common component of cancer treatment. A recent study sheds some light on which patients can safely avoid chemotherapy.

We have known for many years that not all patients who receive chemotherapy will benefit from it – in some cases, less than 3% of patients benefit. We traditionally used measures such as tumor stage, tumor grade, and receptor status such as ER/ PR and Her2/neu. Since 2004, many of us have relied on the OncotypeDx test. This assay, which is performed on the tumor, analyzes 21 genes (of the cancer – different from genetic testing of the patient) that have to do with cell growth and proliferation. The score, which is reported as low, intermediate, or high, is used to help determine whether or not a patient will benefit from chemotherapy.

The initial studies leading to widespread use of the OncotypeDx test were retrospective. Many of the large national breast cancer trials had tissue saved from the original procedures. The OncotypeDx test was run on these tissue samples, and then was analyzed with respect to patient outcomes. Based on these studies, patients with low risk scores were advised not to undergo chemotherapy; chemotherapy targets rapidly dividing cells, and low-risk tumors simply will not respond. Conversely, patients with high risk scores were advised to undergo chemotherapy treatment. Based on these studies, we discovered that our traditional methods of determining who should receive chemotherapy were not very accurate.

A new study published in the New England Journal of Medicine is the report of the first prospective trial involving OncotypeDx testing. Dr. Joseph Sparano and colleagues reported on the Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. In this study, patients with hormone-receptor positive, Her2/neu negative breast cancers, 1.5 – 5.0 cm in size, had OncotypeDx testing on their tumors. Patients with low-risk tumors received endocrine therapy (tamoxifen or aromatase inhibitors). Patients with high-risk tumors received chemotherapy. Patients with intermediate-risk tumors were randomized to either hormonal therapy or chemotherapy, as prior studies did not demonstrate a clear benefit from either class of treatment.

The current study reports on the low-risk group, which included 1626 women. At 5 years, fewer than 2% of patients experienced a local-regional (breast or lymph nodes) or distant / metastatic (spread to other areas of the body) recurrence.

The authors concluded that endocrine therapy is perfectly appropriate for patients with low-risk tumors, and chemotherapy would not add any significant benefit in terms of recurrence or overall survival. A criticism of the study was that follow up was only 5 years, but the authors note that the primary benefit of chemotherapy is in reducing recurrences within the first 5 years of treatment. Endocrine therapy is recommended for longer-term reduction in recurrence in these patients.

Dr. Clifford Hudis, of the Memorial Sloan Kettering Cancer Center in New York, wrote an accompanying editorial: Biology Before Anatomy in Early Breast Cancer – Precisely the Point. He noted that “this assay is the most rigorously tested option and provides proof of the principle that we can develop reproducible predictive results to select patients who should not receive chemotherapy. In that regard, it is one more step towards precision. There are more steps ahead.”