乌鸦传媒

Women age 70 or older account for almost a third (~90,000) of in the U.S. Because of widespread uptake of mammography in the age group, most of the cancers are stage I and have a of hormone-receptor positive/HER2-negative (HR+/HER2-).

Historically, undertreatment of aggressive breast cancer in older women has been a concern, but more recently, studies have shown that overtreatment of small, HR+/HER2- in some older patients can lead to receipt of therapies that are unlikely to improve survival or reduce morbidity.

Increasingly, clinical studies of strategies to reduce locoregional recurrence in older patients have examined ways to reduce the aggressiveness (de-escalate) of breast cancer treatment. However, consideration of de-escalated treatment inherently involves caveats. For example, more than 70% of women ages 70 and older undergo axillary dissection and receive radiation therapy.

"Is this appropriate treatment or overtreatment?" asked Jennifer Tseng, MD, of City of Hope Orange County in Irvine, California, and colleagues in a published in association with the American Society of Clinical Oncology meeting (ASCO). "In thinking about patients who are best suited for de-escalation of axillary surgery or radiation therapy, this management pathway assumes compliance with endocrine therapy. Unfortunately, studies have demonstrated close to one third of patients will have early discontinuation of endocrine therapy."

"For older patients who are of higher risk for early endocrine therapy cessation, radiation gains importance in decreasing risk of locoregional recurrence," according to the authors.

De-escalation can involve surgery, radiation therapy, and/or systemic therapy. Recent advances and continuing progress in breast cancer care have facilitated individualized treatment, which should take into account patient preferences, risk factors, and overall goals of care. Those considerations should take precedence over generalized, uniform recommendations.

Deviation from traditional treatment paradigms to recommend de-escalation can cause considerable discomfort for physicians and patients, Tseng and co-authors noted.

Surgical De-Escalation

As an oncologic surgeon, Tseng considers de-escalation of surgery as "decreasing invasiveness but preserving oncological outcomes," she said during an ASCO education session. "How do I not do harm to my patients while still giving them maximal benefit?"

Several types of surgical de-escalation can figure into treatment plans for older patients with breast cancer. The first is breast-conserving surgery (BCS) versus mastectomy. Multiple studies have shown that the two techniques lead to similar survival and other outcomes for patients with early-stage disease, said Tseng. Incorporation of oncoplastic techniques can help increase the number of patients who qualify for BCS by rearranging tissue or replacing removed tissue to achieve a more natural appearance. Oncoplastics can improve cosmesis, clothing fit, quality of life, and other personal factors.

"Oncoplastic surgery has been proven to be safe," said Tseng. "There's not any increased risk of recurrence. Although it does add time to breast-conserving surgery, it still decreases time in the OR and morbidity for our patients who might otherwise have had a mastectomy."

Reducing or omitting axillary dissection is another common surgical de-escalation strategy. Considering BCS for local recurrence also is a type of de-escalation.

"Do we absolutely have to do a mastectomy for a patient who has a second episode of cancer in the same breast? The answer is no," said Tseng.

Good candidates for BCS and other forms of surgical de-escalation typically have small, localized tumors with favorable tumor characteristics (HR+ and HER2-). These tumors are usually less aggressive and have a lower risk of recurrence. Patients with clinically node-negative disease also might be candidates for de-escalation of axillary surgery. Patients with other health issues, aside from breast cancer, might be more susceptible to surgical complications, potentially making them candidates for surgical de-escalation.

Radiation Therapy

Radiation therapy remains integral to BCS for most patients with early-stage disease, and regional nodal irradiation improves cancer control in node-positive and high-risk node-negative breast cancer. However, improved understanding of breast cancer biologic subtypes and advances in diagnosis and therapy have identified patient subsets who likely derive little benefit from adjuvant radiation therapy.

Several types of radiation de-escalation have proven safe and effective for selected patients with breast cancer. Use of hypofractionation -- administering higher doses in fewer fractions -- in whole breast irradiation (WBI) has become standard of care and can also be used in regional nodal irradiation and postmastectomy radiation therapy.

Hypofractionation has reduced the typical treatment course by about 50%, from 5 to 6.5 weeks to as little as 3 weeks, even less with ultrahypofractionation. Toxicity has been the same or better as compared with standard-dose irradiation.

Hypofractionation is an acceptable alternative to conventional WBI for patients with significant comorbidities or socioeconomic factors that preclude daily treatment, Tseng and co-authors pointed out. The showed that a 3-week hypofractionated regimen offered a good option for high-risk patients requiring a boost to the tumor bed.

Reducing radiation treatment volume by means of partial breast irradiation (PBI) has become an acceptable alternative to WBI for appropriately selected candidates, namely patients ages 50 or older with stage I, node-negative, HR+/HER2- breast cancer. Across all radiation therapy techniques and fractional schedules, PBI seems to reduce 10-year recurrence rates versus WBI in that patient population, noted Tseng and co-authors.

Strategies for omitting radiation therapy continue to evolve. Available data support omission of adjuvant radiation in patients with HR+/HER2- treated with lumpectomy and adjuvant endocrine therapy, said Tseng, but the focus recently shifted to use of genomic and molecular biomarkers to inform the decision-making process. Several ongoing trials are evaluating biomarker-directed strategies to guide omission of radiation therapy in selected patients.

The showed a 5-year local recurrence rate of 2.3% in patients ages 55 and up with grade 1-2 node-negative tumors ≤2 cm with surgical margins ≥1 mm and a low Ki-67 proliferation index.

Several ongoing trials are evaluating omission of radiation therapy in selected patients with HER2+ breast cancer. Several studies previously showed low rates of locoregional and distant recurrence with de-escalated systemic therapy for patients with small, node-negative HR+ breast cancer. The observation has led to a phase III randomized trial comparing adjuvant radiation therapy versus omission of radiation therapy in patients with pT1N0 HER2+ breast cancer treated with lumpectomy, axillary surgery, and adjuvant chemotherapy plus HER2-targeted treatment.

Systemic Therapy

The role of de-escalation of systemic therapy for older patients with breast cancer is more nuanced, as adjuvant therapies require continual dose and/or schedule adjustments for standards established primarily in younger patients, according to Etienne Brain, MD, PhD, of the Curie Institute in Saint-Cloud, France. Frailty is the primary contributor, particularly in patients ages 70 or older. Frailty remains difficult to identify or diagnose accurately and is often overlooked; data suggest frailty is a in up to half of patients ages 65 to 70.

Standards of care evolve from results of clinical trials, wherein "older patients are clearly underrepresented, and this increases alarmingly above 70 to 75 most of the time," Brain said during the ASCO education session. "Importantly, this has not changed in two decades, whether studying new cytotoxic agents, targeted therapies, or IOT [immuno-oncology therapies], even after suppression of upper age limit from eligibility criteria."

Older patients have a higher risk of side effects, regardless of the type of systemic therapy. Pharmacokinetics analyses often fail to reflect declines in functional reserve that occur with aging. The ability to demonstrate a long-term benefit is challenged by life expectancy and comorbid conditions, Brain noted.

Incorporating geriatric assessment into a patient workup can affect treatment decisions in 30-50% of cases, he continued. Two-thirds of the time, decision changes involve de-escalation of initial treatment choices.

Patient expectations for treatment exhibit greater variability with increasing age, with a shift toward preserving physical and cognitive functioning, independence, and quality of life, all of which might be jeopardized by systemic therapies.

"These provocative considerations show [the importance of paying] more attention to expectations expressed by older patients to limit gaps between what is thought by healthcare professionals as right, often on the basis of dose-intensity models strongly ingrained in oncology and that older patients may assess counterintuitively differently," Brain wrote in an in the ASCO education book.

To optimize systemic therapy for older patients, Brain suggested combining the use of molecular testing to identify high-risk luminal breast cancers with a geriatric assessment to "bring relevant global information in the adjuvant setting."

Shared Decision-Making

Shared decision-making has a major role in achieving optimal outcomes in older patients with breast cancer. Over the years, physicians have received more education and training in patient communication, but the discussions need to go beyond laying out the pros and cons of different therapeutic choices, said Mara Schonberg, MD, MPH, of Beth Israel Deaconess Medical Center in Boston.

"We have to communicate the pros and cons in a way that patients can understand and play a role," she told 乌鸦传媒. "We're good at laying out the information ... but really there needs to be more of a revolving process or iterative process, where we're finding out a little bit more about the patients."

"Once you get the hang of it, you might think, 'Oh my God, this is going to take forever.' It doesn't take forever," Schonberg continued. "It's just a style of communication that we haven't done much planning for."

Most oncologic interventions have been validated in younger patient populations, and long-term follow-up may be required to show a benefit for some types of treatment. If a patient is not going to live long enough to realize the benefit, the intervention is only going to cause harm. Prognosis is not a precise science, said Schonberg, but tools have been developed to help determine a patient's life expectancy with reasonable accuracy.

One tool that has gained some traction in oncology is . The instrument elicits information that allows the clinician to estimate a patient's likelihood of surviving over different time periods up to 14 years.

Conversations with older patients often include a relative or caregiver, which creates another variable to consider.

"It can be a complicated relationship," said Schonberg. "Sometimes cancer treatments take a lot of time. Not uncommonly, older patients don't want to be a burden to the caregiver. While the older patient might be making the decisions to try to be less of a burden and not to create conflict because the patient is so dependent on the caregiver for housing or transportation."

"I think the clinician can try to understand what are the dynamics [of the relationship] and what are the motivations, and try to come up with suggestions to address some of the issues," she continued. "It's also important to realize whether the caregiver may have undue influence, but it could be an influence the patient wants the caregiver to have. In those instances, the clinician should remind the caregiver that the decisions should be based on what the patient values and considers important. At the same time, you need to give the family member or caregiver space to share their values."

The most complex conversations usually involve clinical situations wherein the relative benefits versus harms are not so clear.

"We really need to give patients some time, whether it's during a visit or outside the visit, to consider how they feel," said Schonberg. "Are they a 'minimizer' or are they a 'maximizer?' Is this someone who always wants the most aggressive care? Do they want to maximize their time on the planet or their quality of life?"

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