Several studies suggest that it is possible to omit adjuvant radiotherapy after breast conserving surgery, including in elderly patients with low-risk breast cancer. However, a prospective study with patients of all ages and with a pathologically complete response after neoadjuvant chemotherapy was not yet available. The DESCARTES study changes this. Co-principal investigator Dr. Frederieke van Duijnhoven (Antoni van Leeuwenhoek) discusses the study design and expectations.
The omission of adjuvant radiotherapy after breast conserving surgery has been studied in several studies and the results have always been more or less the same. Omitting radiation slightly increases the risk of local recurrence but has no relevant effect on survival. Such findings include the CALGB C9343 study published in 2004 and the PRIME II study published in 2015.1,2 But only a proportion of breast cancer patients were eligible for these studies. In the CALBG study, participants were older women (≤ 70) with HR+ breast carcinoma no larger than 2 cm. And in the PRIME-II study, only relatively older women (> 65 years) with low-risk breast cancer were included (pT1–2; ≤ 3 cm).
“There are various studies that have investigated whether it is possible to omit radiotherapy,” says oncological surgeon Frederieke van Duijnhoven. “Prospective studies have already been carried out in older patients, such as the PRIME II study.2 But the group that the DESCARTES study looks at – patients who no longer have a tumor in situ after neoadjuvant chemotherapy – has only been looked at retrospectively. This group has been studied, for example, in a Japanese retrospective study with about a hundred patients.3 They did not receive radiation and did very well (5-year recurrence rate 1.8%). And a retrospective US study showed that patients who had not received radiation did not have a worse survival (OS 93.6% with radiotherapy and 93% without radiotherapy).4 The aim of the DESCARTES study is to confirm these results in a prospective study.”
Until recently, a study was also conducted in the Netherlands that looked at the omission of radiotherapy in patients with breast cancer. However, the TOP-1 study only focused on elderly patients.5 Van Duijnhoven: “The TOP-1 study was a registration study in people over seventy with a low risk of a recurrence who did not undergo radiation therapy. This is a different group than the group treated neoadjuvant. But the underlying idea is the same, namely that there is a situation in which the chance of a local recurrence is very low and in which the benefits of that radiation probably do not outweigh the side effects and morbidity of this.”
Inclusion and exclusion criteria
The participants in the DESCARTES study also have a low risk of recurrence because there must be a pathologically complete response after neoadjuvant treatment. Van Duijnhoven: “Studies without exception show that the pathologically complete response is the most important factor for a local recurrence. There are other factors that are important, such as whether lymph nodes are affected, but the pathologically complete response is very important, both for the chance of a local recurrence and for survival.” Because the prognosis is favorable in this group, it is ethically justified to de-escalate the treatment, says Van Duijnhoven: “For example, we chose not to include patients with affected lymph nodes in the study. We want to start with a group that is as ‘safe’ as possible.”
Furthermore, patients with all kinds of subtypes of breast cancer can participate. Van Duijnhoven: “In the retrospective studies, we see that it is precisely the triple-negative and HER2-positive breast cancers that have a pathologically complete response. However, there are a number of exclusion criteria: in addition to patients with a risk-increasing mutation such as BRCA, patients with a precancerous stage of breast cancer due to or near the tumor are also excluded from participation. This usually does not disappear completely with chemotherapy, so we prefer not to leave it untreated.”
< 4-6% recidieven
When patients meet the eligibility criteria, they are omitted from radiotherapy and then followed for 5 years with annual MRI or mammography. There is also a one-off follow-up after 10 years. The primary endpoint of the study has been met if a local recurrence occurs in 6% or less after 5 years. Van Duijnhoven: “We expect that around 4 out of 100 patients will experience a local recurrence if we do not administer radiation. Statistically speaking, this means that the recurrence rate must remain below 6. Conversely, you could say that it is expected that 96 out of 100 women will not need radiation.”
“We have taken this percentage on the generous side. For example, if you look at the Japanese retrospective study, with many patients with lymph node metastases and relatively large tumors, the five-year recurrence rate was below 3.5%. DESCARTES is a group with a more favorable prognosis because of the clean lymph nodes and tumors smaller than five centimeters, so we expect to end up below that. We have also discussed this percentage with the patient association. They found a recurrence rate of 4% with a statistical extension to 6% acceptable. However, one patient may find a recurrence rate of 10% acceptable, while another may find 2% too much. In any case, we will soon have a figure that you can present to patients and then make a choice together.”
In addition, there are also various treatment options if a recurrence occurs, Van Duijnhoven emphasizes: “Then you can still have breast-conserving surgery and then radiation. Or you can choose to remove the entire breast, depending on the patient’s preference and the size of the breast and tumor. The idea is that you keep a close eye on the patient, and if something comes back, you can still treat.”
Cancer worry scale
Important secondary endpoints of the study are the quality of life and the level of anxiety and worry resulting from the omission of radiation. Van Duijnhoven: “It could be that if you reduce the treatment, you increase the concerns of patients. If someone constantly thinks: I have not had radiation, would it come back, then it has a counterproductive effect because the aim is to improve the quality of life.” However, the researchers expect that the omission of radiation will have a positive effect on quality of life. “Van Duijnhoven: “Omission of treatment actually by definition increases the quality of life when it comes to pain complaints and cosmetics. It is logical that without radiation you have a nicer breast and less pain. But the downside could be that people are more concerned about a recurrence. We will determine that with the Cancer Worry Scale.”
The outcomes of DESCARTES participants will be compared to a historical cohort. The fact that a randomized study was not chosen has to do with the relatively small differences in whether or not to irradiate, Van Duijnhoven explains. “We expect that the differences in quality of life, although clinically relevant, are not very large. As a result, you have to include a lot of patients to demonstrate a difference between the groups. At the same time, many quality-of-life data of patients who underwent breast-conserving surgery after chemotherapy are already available in the scientific literature. We can compare the results in the field of quality of life with data from other studies.”
Lots of enthusiasm
The study started last year and has now included the first patients. The interest in the research is so great that the number of participating hospitals is being expanded, says Van Duijnhoven. “Initially, the protocol stated that 25 hospitals can participate, but there are so many hospitals that want to participate that we want to expand this to 40 hospitals. So there is certainly a lot of enthusiasm for it and there are now 31 patients in the study.”
This interview appeared in MedNet Oncology – Special Breast Cancer 2023. These articles also appeared in the Breast Cancer Special:
References:
- Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus Tamoxifen with or without Irradiation in Women 70 Years of Age or Older with Early Breast Cancer. N Engl J Med 2004;351:971-7.
- Kunkler IH, Williams LJ, Jack WJ, et al. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015;16:266-73.
- Asaoka M, Narui K, Suganuma N, et al. Clinical and pathological predictors of recurrence in breast cancer patients achieving pathological complete response to neoadjuvant chemotherapy. Eur J Surg Oncol 2019;45:2289-94.
- Mandish SF, Gaskins JT, Yusuf MB, et al. The effect of omission of adjuvant radiotherapy after neoadjuvant chemotherapy and breast conserving surgery with a pathologic complete response. Acta Oncol 2020;59:1210-7.
- Love GJ. 2016-01 TOP-1: Tailored treatment in Older Patients TOP-1: omission of radiotherapy in elderly patients with low risk breast cancer. BOOG, Breast Cancer Research Group, 2016.