**5. Distinctions in the management of systemic therapy in elderly patients**

When conducting oncological systemic therapy in the geriatric population, various side effects may be observed that are directly related to the type of therapy. Depending on the formation mechanism, they may occur with similar or greater frequency than in younger age groups.

However, when treating the elderly, we also encounter problems that are not at all or very rarely described in younger patients. They mainly concern the aging physiology as well as the psychological and sociological levels [14, 15].

The biology of some cancers and their response to therapy changes as the patient ages. In addition, physiological changes associated with aging can affect the tolerance of the drugs. The lower renal and hepatic performance, as well as low bone marrow reserve, which arises from the physiological changes in the aging body, can fundamentally affect the pharmacokinetics and pharmacodynamics of the drugs.

Comorbidities, mainly cardiovascular and nervous ones, are also much more common in elderly patients. Some of those patients may be malnourished and experience geriatric syndromes such as incontinence, tendency to fall, balance disorders, frailty syndrome, and dementia. In addition, in this group of patients, we often deal with polypragmasy [3, 12, 14].

All of these factors can significantly complicate or even prevent optimal systemic therapy. Furthermore, if patients face other types of medical problems, these can significantly define their life expectancy and considerably impair their quality of life [16]. What is of particular importance is the detection of frailty syndrome. Literature data indicate that over half of elderly oncological patients exhibit some or all features of frailty syndrome. This group of patients specifically is often at increased risk of mortality, postoperative complications, and serious side effects associated with systemic therapy, especially chemotherapy [15, 17].

#### *Breast Cancer in the Elderly DOI: http://dx.doi.org/10.5772/intechopen.110293*

Psychosocial factors have been described as having a significant impact on therapeutic decisions and the course of treatment. Elderly patients living alone or with a person of a similar age are less likely to accept possible problems that may arise during treatment.

Similar difficulties may arise for people having difficult access to transportation and those residing in nursing homes. In many countries, governmental or nongovernmental initiatives are emerging to reduce barriers to access oncological treatment among the elderly and disabled. These may involve medical staff visiting the patient at their home to inject or infuse drugs, blood draws for laboratory tests, etc., as well as telephone monitoring of the patient's condition to detect possible adverse symptoms in advance.

Patients with dementia pose a significant problem for oncologists. In most clinical situations, people with minor dementia can understand the rules of the suggested therapy and make proper decisions on their own, if given enough time to explain them properly. In the case of people with more advanced dementia, the caregiver must participate in the decision-making process concerning the therapy and further care provided to the patient.

It should also be pointed out that older patients may prefer therapies that have the potential to improve their quality of life, whereas longer survival may be of lower importance for them. The Silvestri study, for example, assessed the preferences for chemotherapy in patients with advanced lung cancer. Only 22% of patients chose chemotherapy for 3 months' improvement in survival, but the majority (68%) would choose chemotherapy if it substantially reduced symptoms without prolonging life [18].

### **6. Individual approach to systemic therapy in elderly patients**

As the dependencies between genetic and environmental factors in the aging process are quite complex, the aging process for each person is slightly different. Therefore, the chronological age alone does not reflect a patient's condition, nor can it be considered a predictor of response to treatment and the occurrence of side effects or other therapy-related problems. To be able to make optimal decisions about systemic therapy in elderly patients, you need to characterize the functional reserve, both from the physical and mental point of view, as well as assess the number and severity of comorbidities and evaluate the patient's social capabilities [17, 19].

It is also important to make certain modifications, if any, to the treatment of comorbidities, that includes consultations with other specialists, especially in the field of geriatrics, but also rehabilitation, nutrition, etc.

During systemic therapy, it is important to implement any methods that can reduce side effects.

The most important element that is fundamentally responsible for the success of systemic therapy in a group of geriatric patients seems to be the individual assessment of the patient's condition before deciding on their eligibility for therapy. This assessment should be done as early as the initial visit to the clinical oncologist [20, 21].

At present, we have several tools that can help us assess the risk of serious complications arising during systemic therapy. The most commonly recommended tools are the CRASH score and CARG score.

Extermann developed the CRASH score calculator (https://moffitt.org/eforms/ crashscoreform), which can be used to assess the risk of serious chemotherapy

complications among elderly patients based on information about the planned therapy and patient characteristics. The main elements indicating the risk of hematologic toxicities are the instrumental activities of daily living score (IADL), blood lactate dehydrogenase level, diastolic blood pressure value, and estimated toxicity of the chemotherapy regimen. In contrast, the incidence of serious non-hematological complications is supported by the patient's ECOG score, cognitive status using the mini-mental state examination (MMSE) score, nutritional status using the mininutritional assessment (MNA) score, and the toxicity of the therapy regimen [22].

Huria was the author of a similar tool, namely the CARG score calculator (https:// www.mycarg.org/?page\_id=934 or https://www.evidencio.com/models/show/520), which can be used to assess the risk of serious complications of systemic therapy based on such information as the patient's condition (age, the number of falls they have had within the past 6 months, limited social activity, and need for assistance with medications), laboratory test results (creatinine and hemoglobin levels), and the proposed therapy regimen. In addition, Huria emphasized that the Karnofsky Performance Status (KPS) commonly used by oncologists to assess the performance status of the elderly is not useful at all [23].

Recently, we have observed some opinions that point out the importance of optimizing psychosocial and physical health before starting systemic therapy in older patients. This involves the identification of patient's needs in this regard. The International Society of Geriatric Oncology (SIOG), an organization dedicated to addressing oncology issues in the elderly, recommends conducting a comprehensive geriatric assessment (CGA) before undertaking any planned surgical intervention or systemic therapy in elderly oncological patients. The value of this assessment lies not only in determining the risk of possible complications but primarily in seeing it as a possibility of optimization and individualization of treatment [3, 19].

Kalsi published the results of a randomized trial involving 135 cancer patients over the age of 70 years who were eligible for chemotherapy. The observational control group (70 patients) received standard oncological therapy, while the intervention group (65 patients) underwent risk stratification using a patient-completed screening questionnaire; subjects were assigned to appropriate groups, depending on the risk of complications. Those at high risk of complications had a comprehensive geriatric assessment performed and, based on the results, were given plans for appropriate multidisciplinary interventions. It turned out that patients in the intervention group were more likely to follow the expected treatment plan and were less likely to require any modification of therapy [10, 24].

Thus, there seems to be a need to change the approach to oncological therapy of elderly patients taking into account the need to implement measures currently referred to as prehabilitation [25].

#### **7. Surgery and radiotherapy for breast cancer**

Unquestionably, unless there are very significant contraindications to anesthesia, stage II, post-neoadjuvant therapy breast cancer patients (and in selected cases stage III patients that have not received neoadjuvant therapy) should be offered surgical therapy, which may involve breast-conserving surgery or mastectomy.

In selected cases, i.e. in patients with a predicted survival time shorter than 5 years, axillary procedures as well as any surgical treatment in general may be abandoned when the preinvasive form of breast cancer has been diagnosed.

#### *Breast Cancer in the Elderly DOI: http://dx.doi.org/10.5772/intechopen.110293*

However, studies have shown that surgical treatment is often abandoned in elderly patients for various reasons. The study of Bastiaannet et al., which involved more than 120,000 women, showed that older age was associated with a lower percentage of surgeries. Whereas more than 93% of women under 80 years of age underwent surgery, the percentages of radical breast cancer surgery performed in the 80–84, 85–89, and over 90 years of age groups totaled, 83%, 65%, and 41%, respectively. Also, it has been shown that older patients were less often eligible for radiation therapy after breast-conserving surgeries. In that group, in women under the age of 75 years, radiotherapy was used in more than 90% of cases, while in the age groups of 75–79, 80–84, 85–89, and 90+ years, it totaled 86%, 71%, 36%, and 15%, respectively. However, this study does not report on how the decision of radiotherapy was dependent on cancer recurrence risk factors. The same paper claims that the eligibility for hormone therapy (without surgical treatment) rate increased with age. It ranged from <1% in patients below the age of 65 years up to 47% in patients aged 90 years and older [26].

Another study attempted to answer the question of whether the lower number of surgeries performed arose from the functional status or biological age of patients with stage I, II, or III breast cancer. Multivariate analysis showed that women aged 85 years and older were significantly less likely to undergo breast cancer surgery having taken into account the patient's possible negative attitude toward the procedure and their functional status (the odds ratio [OR]: 0.18, 95% CI 0.07–0.44). These data suggest that objective considerations are not always decisive when assessing older patients' eligibility for surgery [27].

Most patients without functional status limitations should be eligible for adjuvant radiotherapy following breast-conservative surgery. However, it should be noted that even during the visit to discuss surgical treatment options with the patient, they should be informed of the radiation therapy options, as some patients may decide not to have radiation therapy for the fear of its consequences or for social reasons [28].

### **8. Systemic perioperative therapy**

Older patients with early forms of breast cancer and perfect or very good functional status may be offered adjuvant therapy per standard treatment guidelines for younger patients. In the case of patients with multiple internal concomitant diseases, cognitive disorders, and functional status limitations, the suggested therapy should mainly depend on the feasibility and expediency of surgical therapy. If surgery had been performed, in most patients with an estimated survival time of up to 5 years, systemic therapy and radiotherapy may be abandoned. On the other hand, those patients that do not agree to surgery or who cannot have surgery due to medical contraindications should receive hormone therapy (in case of hormonesensitive cancers) or remain under the supervision of an oncologist or a general practitioner (GP).

It is believed at present, that breast cancer patients aged 65–70 years should be initially evaluated in terms of their general condition and internal diseases by an oncologist, and only the preselected patients should undergo geriatric screening tests (mainly to evaluate their functional status). To this end, it is recommended to use the G8, VES-13, TRST 1+ scales, or Groningen Frailty Index. This evaluation should be also performed for all older patients. In the case of some patients, the next necessary step before making any decisions about the therapy may be a comprehensive geriatric evaluation and geriatric consultation [29–31].

This will help to select a group of older patients who should be eligible for or totally excluded from chemotherapy. Additionally, the International Society of Geriatric Oncology (SIOG) guidelines suggest the need for serial evaluation of functional status during adjuvant therapy to identify deterioration of the patient's health and undertake necessary intervention as early as possible [24, 32].

#### **8.1 Fit patients**

The treatment management of fit older breast cancer patients is identical to that of younger women and depends primarily on the evaluation of the recurrence risk factors. As a general rule, some patients should be offered neoadjuvant therapy.

The preferred cytostatic agents for perioperative treatment in this group of patients are anthracyclines and taxanes. However, you should remember the risk of myocardial damage after anthracyclines; therefore, women with significant cardiac comorbidities should be excluded from therapy with this group of cytostatic agents.

The study conducted by Pinder et al., which included 44,338 women aged 66–80 years with stage I–III breast cancer with no history of heart failure, showed that with a follow-up median of 56 months, evidence of heart failure after 5 and 10 years after the end of treatment in the group of patients who received anthracyclines (4000 patients) totaled 19% and 38%, whereas in the case of patients that did not receive anthracyclines, they totaled 18% and 33%, respectively. In the case of patients who did not receive any chemotherapy, it totaled 15% and 29%. Heart failure symptoms were observed more frequently in Black patients, as well as in patients with hypertension, diabetes, and coronary artery disease [33].

Other options involving slightly less cardiotoxicity are epirubicin or liposomal anthracyclines.

In patients who cannot receive anthracyclines, a TC (docetaxel with cyclophosphamide) regimen can be used. In a randomized phase III clinical trial published in 2009, four cycles of TC were shown to produce superior median progression-free survival and median overall survival compared with four cycles of AC, in patients with stage I–III cancer aged 65 years and older [34].

Another option is a CMF regimen (cyclophosphamide, methotrexate, 5-fluorouracil), but this is not the preferred option due to the high risk of hematological complications in elderly patients [35].

Where we are dealing with patients with lower performance status or significant internal comorbidities, a reasonable option may be paclitaxel administered weekly for 12 weeks at a dose of 60–80 mg/m2 [36].

Single-agent capecitabine is not recommended as adjuvant therapy in elderly patients. A randomized phase III trial involving 633 patients aged 65 years and older with early-stage breast cancer, which was published in 2009, showed that capecitabine produced worse therapy results. During the follow-up (a follow-up median of 2.4 years), a progression-free survival rate totaled 68% versus 85%, whereas an overall survival rate was 85% versus 91% after a follow-up median of 3 years [37].

Adjuvant therapy combined with trastuzumab and taxanes is recommended for breast cancer patients with overexpression of HER2. Sequencing of anthracyclines is usually not recommended due to the increased risk of heart failure.

Data on the use of docetaxel and carboplatin in combination with trastuzumab, as well as with trastuzumab and pertuzumab, are very limited in women aged 70 years and older. Rather, a TC (docetaxel with cyclophosphamide) regimen should be

#### *Breast Cancer in the Elderly DOI: http://dx.doi.org/10.5772/intechopen.110293*

considered in selected cases in patients with no functional status limitations and higher-stage cancers.

Also, in the case of HER2-positive cancer patients, chemotherapy can be often limited to paclitaxel administered weekly for 12 weeks. In contrast, for patients diagnosed with stage I and II hormone-sensitive, HER2-positive cancer, hormone therapy in combination with trastuzumab may be a sufficient treatment option [37, 38].

For patients with cardiovascular comorbidities, consideration may be given to shortening the length of trastuzumab therapy, as trastuzumab-induced cardiotoxicity is linked to the length of exposure [38, 39].

Until now, there are no guidelines pertaining to the group of older patients regarding prolonged anti-HER2 cancer therapy with neratinib, nor the use of trastuzumab emtansine for the minimal residual disease after the completion of neoadjuvant therapy.

Preoperative hormone therapy is recommended for patients with hormone-sensitive cancers at a locally advanced stage, or for those interested in conserving therapy but whose anatomical conditions prevent it at the time of breast cancer diagnosis. The recommended group of drugs in this case is aromatase inhibitors. They should be administered for 6–9 months and, of course, should be continued after the surgery, as long as the response to therapy is observed [40].

Adjuvant hormonal treatment should be offered to all patients with hormonesensitive breast cancer, regardless of age. Aromatase inhibitors are preferred in older women due to the greater benefit of such treatment in this patient group versus tamoxifen and a more favorable safety profile. However, for patients at high risk of cardiovascular complications and with advanced osteoporosis or aromatase inhibitor intolerance, tamoxifen is also a reasonable option.

The optimal duration of adjuvant hormone therapy is not fully established. The minimum therapy duration should be 5 years, but in selected patients, it may be recommended to extend the therapy up to 10 years [41, 42].

#### **8.2 Patients with evidence of frailty syndrome**

Patients with evidence of a frailty syndrome, short life expectancy, and those wishing to avoid any therapy-related toxicities should be treated on a case-to-case basis [43, 44].

In some patients, systemic therapy can simply be abandoned (except for hormone therapy in hormone-sensitive cancer patients).

Also, in this group, aromatase inhibitors as hormonal therapy are preferred, but there are no results of prospective studies in this patient population comparing the efficacy and safety of tamoxifen versus aromatase inhibitors.

Similarly, no results of randomized trials comparing more aggressive treatments with hormone therapy, or hormone therapy only, have been published.

#### **8.3 Metastatic breast cancer**

Metastatic breast cancer remains incurable regardless of the patient's age, and any available therapy is palliative. Only about 20% of metastatic patients survive 5 years.

However, even in older patients with metastases, there is a high risk of death from causes other than breast cancer [8, 12].

The goal of therapy in metastatic patients is to maintain the highest quality of life for as long as possible.

#### **8.4 Triple-negative cancer**

The general approach to treating older patients with metastatic triple-negative breast cancer is similar to that followed in younger patients; it consists of using single agents sequentially, except for patients with rapidly progressive symptomatic metastases [45].

Radiation therapy should be considered for older patients with symptomatic brain and bone metastases.

Older age has been proven to be a risk factor for early death in those who present with de novo metastatic triple-negative breast cancer.

In a group of older patients, several single agents are recommended as preferred single agents. These include capecitabine, weekly paclitaxel, nab-paclitaxel, eribulin (as second- and third-line treatment), liposomal doxorubicin, vinorelbine, and gemcitabine [34, 45, 46].

The choice of drug should be based on the toxicity profile. As first-line therapy, response rates vary greatly according to patient characteristics, and average about 30–50%, while progression-free survival time averages about 3 to 6 months. Secondand third-line therapies are less effective.

In comparison with younger age groups, the use of chemotherapy in patients aged 80 years and older has been shown to be associated with a significantly higher rate of hospitalizations (32%), red blood cell concentrates transfusions (18%), and reduced doses of cytostatic drugs, skipping and/or delaying subsequent doses (68%) [47, 48].

Other drugs that can be considered for the treatment of elderly patients include olaparib (poly(ADP-ribose) polymerase inhibitor). However, as with most trials of newer agents, the registration study of that drug in breast cancer patients involved only 15 patients aged 65 years and older [34, 49].

Modulating the immune system using checkpoint inhibitors also shows promise, but almost no data are available from randomized clinical trials in older breast cancer patients [50].

#### **8.5 Hormone-dependent cancer**

The primary treatment option for generalized hormone-dependent breast cancer is hormone therapy. Preferred options for first-line therapy are aromatase inhibitors or fulvestrant. In most cases, hormone therapy may be combined with cyclin-dependent kinase 4/6 inhibitors. A particular agent from this group should be selected depending on the expected side effects. Most authors suggest that palbociclib may be the agent best tolerated by elderly patients [51, 52].

The second-line therapy should include a hormonal drug that has not been used yet in combination with a CDK 4/6 inhibitor (provided it has not been used before). The combination of hormone therapy with alpelisib is also recommended in older patients with PIK3CA mutations [53].

In the case of patients with hormone resistance, chemotherapy is also an option, according to standard guidelines for patients with triple-negative cancers.

#### **8.6 Cancer with overexpression of the HER2 receptor**

For older patients with HER2-positive cancers, pertuzumab, trastuzumab, and a taxane are recommended as first-line therapy options, similarly to younger age groups, whereas paclitaxel is the preferred option in this case [37, 49].

*Breast Cancer in the Elderly DOI: http://dx.doi.org/10.5772/intechopen.110293*

Patients with poorer functional status may be considered for pertuzumab and trastuzumab in combination with cyclophosphamide administered orally at a dose of 50 mg/day [54].

The combination of dual anti-HER2 blockade with an aromatase inhibitor is also a recommended option in patients with HER2-positive hormone-sensitive cancers.

In the next line of therapy, trastuzumab emtansine (T-DM1) is recommended due to the good safety profile of this drug in the elderly patient population.

For patients with good functional status, other drugs that act on the HER2 receptor may be considered, but information on the safety of these drugs in the group of patients older than 65 years is very limited [47, 49].

#### **8.7 Patients with evidence of frailty syndrome**

Patients with generalized breast cancer and evidence of frailty syndrome, significant cognitive disorders, or multiple co-existing internal diseases should be treated on a case-to-case basis. It should be noted that the proposed treatment must not cause more problems for the patient and her family than the cancer itself. Therefore, sometimes the best option may be to use symptomatic therapy only in hospice-palliative care [55].
