Review Article a Multidisciplinary Evaluation for Advanced Supportive Care of Breast Cancer Patients

Abstract

Background

Cancer cases diagnosed each year are increasing, mainly because the population is ageing and, in part, due to early detection. This implies that there are more and more persons that receive medical anticancer therapies and that are interested in maintaining their quality of life. Many oncological treatments, including chemotherapy, immunotherapy, surgery, and radiotherapy, and combined therapy are associated with cutaneous toxicity and long-term side effects to different tissues and organs. This is particularly relevant when new therapies are used since these may cause new and unexpected side effects that may be short-lived but, in some cases, may become chronic or permanent. Patients often seek advice with their oncologists on what can be done and what cannot be done. Notably, many of the cutaneous side effects can be prevented or reduced by adequate interventions.

Summary

The aim of this review is to highlight how oncological patients may benefit from a closer collaboration between specialists in different branches. We will focus on women with breast cancer since we think that they may derive a special benefit from this collaboration, but we will analyse other cancers in future papers.

Key Messages

The working group was created to help the medical doctor in the prevention and management of all the adverse effects of the oncological treatments, supporting patients in this phase of their life, including nutritional assessment and dietary support.

Introduction

Annual incidence of all tumours can be estimated around 190 cases/100,000 with a cure rate of approximately 65%. Breast cancer is the most common cancer in women. About 287,850 new cases of invasive breast cancer will be diagnosed every year in the USA [1]. Thus, the number of cancer survivors has reached considerable numbers, accounting for 9.8 millions and 12 millions individuals in the USA and in Europe, respectively [2]. This marked increase in survival is mainly due to earlier diagnosis and better treatments, but many survivors live with acute and chronic consequences of those treatments, including cardiotoxicity, secondary tumours, and infertility [3, 4]. Moreover, the psychological implications of diagnosis and treatments on patients and their families should not be ignored. Adverse effects (AEs) may include any organ or apparatus, thus more specialists are needed to offer uniform and shared diagnostic and therapeutic care paths [5]. The prevention and management of these side effects represent a crucial point to obtain optimal care that should include every feature of the patient's health and not only the treatment of cancer [6]. In addition to being frequently disabling, skin and annexa damages including alopecia, skin rashes, or skin alterations are certainly the most visible and assessable by the patient [7], producing an important psychological impact, alteration of body-image, cultural and gender identity, sexuality, and health-mind relationship [8, 9]. For these reasons, toxic side effects involving the skin and cutaneous adnexa, given by different pathogenetic mechanisms depending on the drug, are considered more and more relevant [10]. On the other hand, it is widely accepted that the skin signals reveal what happens within the body: the skin can be considered “a great sentinel” [11] and its monitoring during anticancer treatment is therefore very important [12]. The frequency of dermatological AEs depends on the agent administered and less frequently on tumour type, 18–72% of patients show dermatological AEs during cytotoxic chemotherapy, 75–90% [13] during target therapy and >30% of patients in immunotherapies [14]. Radiotherapy causes a variety of side effects, commonly referred to as radiodermatitis that can range from mild erythema to severe confluent moist desquamation. All patients receiving radiotherapy are at risk of developing these reactions [15]. Therefore, early assessment and management promote patient comfort and enhance quality of life (QoL). Combining radiotherapy and systemic therapy may exacerbate cutaneous reactions, resulting in severe xerosis, inflammation, skin thinning, and necrosis of the upper dermis and epidermis. Side effects tend to appear early on, and although mostly mild at onset, can become severe and significantly impair QoL [6]. These reactions may lead to dose reduction or discontinuation of therapy, which could be detrimental to the outcome of treatment. The correct diagnosis and management of dermatological AEs are crucial, both to optimize therapeutic success rates and to reduce the patient's suffering [16]. We are therefore witnessing the evolution of the concept of “cure” into “taking care,” at the basis of the new holistic vision of the patient, which focuses not only on the disease burden, but also on additional therapeutic goals, as (QoL) [17], a previously ignored factor, but which now seems to be crucial for patient's prognosis [7, 18]. The appearance of severe cutaneous AEs can lead to a decrease in drug dosage, and in some cases to discontinuation of therapy [19]. The heterogeneous clinical pictures that can arise during treatment are generally linked to the mechanism of action of the agents, but since drugs are often used simultaneously in polychemotherapy regimens, cumulative toxicities may appear [20, 21]. It is therefore understandable that cutaneous AEs are frequently unpredictable since they can also be worsened by the interactions with supportive treatments including antibiotics, antiemetics, analgesics, or antidepressant drugs [22]. In this complex scenario, a multidisciplinary team (MDT) plays a crucial role in providing optimal care for breast cancer survivors [23, 24]. Professionals, as the oncologist, the surgeon, the radiotherapist, are supported by the nutritionist, the endocrinologist, the gynaecologist/andrologist, the pain therapist, the aesthetic specialist, the dermatologist, and other figures, previously erroneously considered of secondary importance. Here, we propose the onset of a MDT in which all these health care providers cooperate to “take care” of their patients. To simplify, the specific case of patients affected by breast cancer will be used as an example.

Dermatological Toxicity

Concerning the toxic side effects of chemotherapy on the skin and cutaneous annexa, they may comprise hair thinning and hair loss and alterations of oral and any mucosae. Here, we will focus on drugs that are commonly used in the treatment of breast cancer. The most evident example is alopecia (hair loss) which is inevitably caused by anthracyclines and by taxanes [25]. Docetaxel may also damage nails, and this may be a cause of relevant stress for some patients [26]. Fluorouracil and capecitabine may cause reddening and tenderness of the palms and of the soles (hand-foot-syndrome), as also observed with liposomal formulations of doxorubicin [27]. Hyperpigmentation may also be associated with the hand-foot-syndrome, while flagellated dermatitis, a fairly specific form of hyperpigmentation, is reported only with bleomycin. It is important to note that hormones may also be associated with cutaneous damage which is due to the decrease in oestrogen levels caused by luteinising hormone-releasing hormone analogues and by aromatase inhibitors. Xerosis is very common during almost all oncological treatments [28], so the main goal of this phase is to maintain physiological skin homeostasis in the best possible condition. Therefore, the correct preventive measures should be adapted according to the planned oncological regimen and the cutaneous or systemic comorbidities of the patient.

Nails can also be damaged by anticancer agents, and for this reason, preventive measures may be useful. General preventive recommendations should be suggested to all oncological patients, while specific protective measures may be proposed according to the different protocols. The preventive approach can be supported by professional figures to perform, for example, correct nail management and to reduce elements that may predispose to damage [29, 30]. Concerning the effects on hair follicles, there are several types of treatment-induced alopecia, according to the different oncological protocols (classic chemotherapy, target therapies, hormonal therapy, immunotherapy, and radiotherapy) [31]. Notably, alopecia in women almost invariably has a strong emotional impact and represents one of the most common reasons of chemotherapy refusal or scarce compliance [12]. General preventive measures have been suggested such as scalp cooling or local vasoconstrictors, the rationale is the decrease in drug delivered to the follicular unit. Scalp cooling, to date, is the only Food and Drug Administration approved useful intervention able to prevent classic chemotherapy-induced alopecia with an effectiveness of 50–80% [31, 32, 33, 34]. This preventive measure has unsatisfactory results in the other type of chemotherapy-induced alopecia.

Besides the toxic effects on the skin tissue, even mucositis represents one of the main AEs of chemotherapies. Mucositis may be caused by different drugs, and it may be different according to the anticancer treatment administered, as, for example, taxanes, anthracyclines, irinotecan [35]. It is important to underline that the mucosae are not just limited to the oral cavity, but they line the entire gastrointestinal tract, the urogenital tract, and the eyes; therefore, these areas must also be considered [36]. The prevention of oral mucositis is very relevant since a severe involvement can interfere with the patient's ability to eat and more importantly to drink and may contribute to the worsening of the general conditions and therefore of the prognosis [37]. Recent studies focused the attention to the oral and intestinal microbiota that could be relevant to mucositis development and treatment [38], but no clear high-risk pattern has been identified and no single probiotic formulation has emerged from human clinical trials for strong recommendation. Noteworthy, mucositis caused by chemotherapy are due to damage to proliferating cells in mucosal crypts: bacteria or fungal infection of the damaged mucosa can certainly occur but starting antifungal treatment for any oral mucositis is not advisable [39].

Aesthetic Medicine to Support Oncology

The objective of good management of side effects during chemotherapy is to correctly diagnose and treat any possible cutaneous AEs to avoid drug dose reduction or discontinuations, as well as to maintain the patient's QoL [40]. Xerosis, itching, different kinds of rash, bullous lesions, acral erythema, photoreactions, cutaneous and mucosal pigmentations, nail alterations, mucositis, and alopecia are just some of the clinical manifestations during therapy [41]. Some new forms are now emerging during immunostimulating therapies: vitiligo, lichenoid reaction, bullous dermatoses, maculopapular rashes, and life-threatening severe cutaneous adverse reactions [42]. Several publications provide recommendations or algorithms for pharmaceutical treatment, but skincare itself remains unclear and not sufficiently detailed. What is certain is that a close and timely collaboration between the different specialists would ensure that the best decisions are made for patients, with the aim of managing adverse dermatological reactions from the beginning of treatment to ensure continuation of therapies without suspensions, changes, and interruptions of treatments [6, 23]. Therefore, in a multidimensional and multidisciplinary evaluation, aesthetic medicine, which has always been attentive to “skin health,” plays an important role for prevention and cure [18, 43, 44]. In particular, the preventive role of aesthetic medicine focuses on maintaining the integrity of the skin during oncological treatments with basic dermo-cosmetic therapy: this must include cosmetics for correct cleansing, care and photoprotection [45]. The role of the treatment of skin damage is to monitor, evaluate and treat acute and late toxicity from mild skin discomfort to medium-grade toxicity with advanced dermo-cosmetic therapies [46]. A constant dermo-cosmetological vigilance can avoid annoying skin sequelae; therefore, a greater awareness of the oncologists regarding the need for the precious support of specialist dermatologists, aesthetic doctors, and cosmetologists even before the start of oncological therapies becomes fundamental, with a “skin care” protocol that prepares the skin for the extreme stress that awaits it [47, 48]. Indeed, skin compatibility is an essential requirement of any cosmetic prescribed to cancer patients whose skin is often more delicate and may have been weakened by previous lengthy treatments or may in any case be suffering from diseases already present before the start of oncological therapies [49]. Before recommending a cosmetic product or treatment, a careful preliminary medical history must be carried out as it is necessary to respect the skin's hydrolipidic mantle and its sensitivity in the daily routine [6, 46]. It may also be useful to carry out an “aesthetic skin check-up,” characterized by a series of clinical and instrumental evaluations, to help the aesthetic doctor in prescribing the best cosmetic support therapy during therapies and post-treatment [50]. An “aesthetic skin check-up” as recommended in aesthetic medicine aims at clinically evaluating the skin using tools that allow the recording and monitoring of physiological parameters over time, including the use of equipment before, during and after oncological treatments [51]. The parameters that can be evaluated are, among others, corneometry that is an estimate of the water content of the stratum corneum; sebometry which is an accurate and reproducible measurement of the sebum level of the skin surface and Ph. Also measurement of skin elasticity based on the method of suction/elongation and subsequent skin release and measurement of melanin and haemoglobin with instruments, allow the evaluation, through reflectance spectrophotometry, of the two main components responsible for skin colour, melanin and haemoglobin (erythema) [51, 52, 53]. Therefore, aesthetic medicine is crucial for the management of cancer patient, in order to evaluate the skin parameters and set the “tailor-made” support therapy to guarantee a condition of equilibrium and to monitor the variations in an objective way [54].

Nutritional Assessment

Until recently, nutritional care was not considered a critical issue in patients immediately after cancer diagnosis. Indeed, some researchers believed that nutrition could have stimulatory effects on tumour growth [55, 56]. Some of these beliefs were based, in part, on the results of in vitro or in vivo animal research [57]. Recently, DeWys et al. [58] have shown that without adequate nutrition, malnutrition, and weight loss in people with cancer could represent a major cause of mortality. This pioneer study paved the way for new therapeutic approaches to cancer patients, also based on nutritional support. In recent years, the concept that an increase in body weight in breast cancer patients (BCP) represents a risk factor associated with comorbidities clearly emerged [59]. Therefore, it would be appropriate for BCP care that nutrition experts encourage weight management during all phases of cancer care [60, 61, 62, 63]. In women with breast cancer (especially those in the pre-menopausal stage), weight gain usually affects them in the early stages (grade I or II) of the disease [64, 65]. In addition, changes in body composition can negatively affect the nutritional status of patients, increasing the risk of tumour recurrence and death [66, 67, 68]. It should also be kept in mind that the nutritional status of BCP changes during treatments [69] for different reasons, as tumour size, digestive symptoms, increased nutritional needs, and erroneous belief of what a healthy diet represents [70, 71]. Antineoplastic treatment induces a decrease in bone mineral density and an increase in body weight, mainly due to an increase in fat mass and a decrease in muscle mass and strength, also known as sarcopenic obesity [65, 71, 72]. Thus, nutritional therapy could improve and prevent adverse changes in the body composition of BCPs in the early stages of the disease [73, 74, 75, 76, 77]. From the studies cited so far, and according to the clinical practice guidelines for overweight and obesity and with the recommendations for cancer survivors, the following nutritional interventions for BCPs should be addressed: (1) limit weight loss to between 5% and 10% of initial body weight by calorie restriction based on age and initial body mass index, (2) increase diet quality with nutrient-rich foods, and (3) reduce simple sugars and added fats [78, 79, 80, 81]. In addition, even normal-weight BCP patients should still receive appropriate nutritional therapies to prevent weight gain, nutrient deficiencies, and adverse health consequences [65, 82, 83]. Nutritional therapy for weight loss aims at achieving a negative energy balance in an individual's total energy requirements by increasing physical activity and reducing dietary energy intake. Calorie restriction will depend on the patient's nutritional status, but a usual therapy may consider a reduction of 500–1,000 kcal/day. Most behavioural programs are designed to achieve a loss of 0.5–1 kg/week, encouraging patients to be engaged in a healthy nutritional behaviour [79, 84, 85]. Since specific nutritional guidelines for BCPs are still lacking, the American Cancer Society suggests a nutritional approach based on guidelines published in 2000 by the National Institutes of Health in the USA [85]. These guidelines provide more specific nutrient recommendations (fat intake, carbohydrates, fibre, cholesterol, etc.) for BCP, and their strength lies in the consideration of caloric restriction to promote healthy weight loss [86, 87], providing proper macronutrient distribution to customize the patient's eating plan. For body weight control in BCP, the American Cancer Society recommends a healthy low-fat diet (<30% from total energy) with a strong fruit and vegetable base (5–9 servings/day) and encourages physical activity [88]. Within this context, one multicentre study reported that only 30–48% of people newly diagnosed with BCP made positive changes in their eating habits. These changes included increasing consumption of fruits and vegetables and reducing consumption of fats and simple sugars. Nevertheless, nearly half of newly diagnosed BCP patients do not introduce these positive changes into their lifestyle [89]. Furthermore, an evidence-based nutrition intervention program proposed by the Oncology Nursing Society and supported by the National Cancer Institute recommends individualized nutrition therapy as the most effective measure for cancer patients. The nutritionist in such therapy should work together with the patient, his or her family, and a multidisciplinary oncology team to provide appropriate nutritional assessment and follow-up of the intervention [86, 90]. The evidence-based ESPEN guidelines were also drafted to translate the best current evidence and expert opinion into recommendations for MDTs responsible for identifying, preventing, and treating the reversible elements of malnutrition in adult cancer patients [91].

Nutraceuticals and Food Supplements

Several recently published papers show that antioxidants can play an important role in preventing breast cancer and can positively affect the therapeutic interventions [92]. Melatonin [93, 94, 95, 96], resveratrol [97, 98, 99, 100], curcumin [101, 102, 103, 104], vitamins C [105, 106, 107, 108], D [109, 110, 111, 112], and E [113, 114, 115] and even synthetic antioxidants such as N-acetyl cysteine [116, 117, 118] have been studied with the aim of evaluating their real effectiveness. While we have a great deal of in vitro evidence, clinical trials are still lacking, and often not set up in a consistent way. It is essential to appropriately stratify patients in relationship to the tumour isotype, and consider the chemical interactions between pro-oxidants and antioxidants (“redoxidomics”), to define the optimal dosage of these molecules for a personalized medicine [92]. Another issue concerns the study of interactions between different types of antioxidants according to their origin. Noteworthy, exogenous antioxidants carry out their actions in aqueous phase (e.g., vitamin C) or in lipid phase (e.g., vitamin E) and are in redox balance between them and with endogenous antioxidants (e.g., glutathione) in preventing or repairing oxidative damage on biochemicals or cell components (e.g., plasma membranes) [119]. Many studies have also highlighted the “multitarget” role of some antioxidants especially with polyphenolic structure. Molecules as quercetin, for example, in addition to the ability of reactive oxygen species scavenging, possess anti-inflammatory, gene modulation, and anti-proliferative properties [119]. These molecules, found in different foods, behave as real drugs and are often defined as “nutraceuticals.” The term “nutraceutical” combines two words: “nutrient,” a food component, and “pharmaceutical,” a drug. The term was coined in 1989 by Stephen De Felice, chairman of the Foundation for Innovation in Medicine. Unfortunately, while studying the antioxidant effects in vitro is very simple, unravelling the potential anti-proliferative properties towards breast cancer or the dose-response relationships is much more complex. Poschner and collaborators [98] investigated the role of resveratrol and other polyphenols in inhibiting oestrogen metabolism in human mammal cellular lines (ERα+ and ERα‒). Experimental results highlight that only high concentrations of polyphenols can inhibit the proliferation of cancer cells while low concentrations could even stimulate cell growth [98]. A similar behaviour was demonstrated by Patisaul and Jefferson [120] for phytoestrogens, as the genistein, that only at high doses is able to inhibit the proliferation of cells ERα + and ERα‒ while, on the other hand, promoting proliferation at low doses. This evidence, related to the dual action of resveratrol and genistein, appears to be particularly worrying in the light of the current market trend that proposes phytoestrogen supplements as isoflavones, for a preventive and protective role towards breast cancers. These suggestions were not (yet) supported by strong clinical evidence. For this reason, foods such as soy, rich in isoflavones, should be cautiously consumed by women with a high risk of developing breast cancer as they still lack studies on their biological actions at cellular level [121]. These results show how dietary supplementation with polyphenols in the prevention and treatment of breast cancer is currently controversial, once again due to the lack of clinical trials aimed at mainly defining the posology. In vitro research, does not allow to study pharmacokinetics and bioavailability of antitumor nutraceuticals, being unable to dissect the interactions with the microbiota and with the immune system as well. The microbiota, able to produce immunomodulatory and antineoplastic molecules [122], could convert nutraceuticals (prebiotics) into metabolites with anticancer properties. Some vitamin deficiencies can worsen the clinical history of patients with breast cancer. A meta-analysis performed by Harris and collaborators [105] highlighted that a post-diagnosis vitamin C supplementation could be associated with a decreased mortality in patients with breast cancer. Even the presence of adequate quantities of vitamin C in the normal diet of patients before the diagnosis seems to be associated with a decrease in total mortality associated with cancer. Another meta-analysis performed by Hossain and Coworkers [112], demonstrated that vitamin D dietary deficiencies can promote the onset of breast cancer while a supplementation exerts a protective effect. Nevertheless, besides these encouraging results, the evidence to support vitamin supplementations for preventing breast cancer is still limited. Miotti and Gnagnarella [123] and Mokbel [124] highlight that, despite several biological mechanisms have been clarified, there is still no clear evidence concerning the role of vitamin supplementation in decreasing the risk of mammary cancer onset. This limitation could be overcome through well-structured clinical trials. Similar conclusions were reached by Avila-Galvez and co-authors about the preventive role of polyphenols [125] and Gonzalez-Gonzalez et al. [93] about melatonin. Some components of the Mediterranean diet, as resveratrol, retinoids, epigallocatechin 3-gallate, and omega-3 PUFAs could represent innovative anticancer candidates. However, few data are available on the potential role of nutraceuticals and food supplements during anticancer therapy or as potential chemotherapeutic agents [126].

Conclusion

Patients with cancer undergo a variety of oncological treatments, including surgery, radiation, traditional chemotherapy, targeted immune checkpoint inhibitor, and endocrine therapies. Many of the pathways targeted by anticancer therapies are also important for skin, hair, mucosal, and nail homeostasis; therefore, dermatological toxicities are among the most frequently encountered AEs. When severe, these conditions may result in interruption of cancer therapy, and late or persistent complications can arise. According to QoL studies, women are affected to a greater degree than men by the toxic dermatological effects of cancer therapy [4, 7, 9, 10], and these toxicities can affect a woman's self-image, cultural identity, femininity, sexuality, and mental health [127, 128, 129]. Recognition and management of these late effects, focusing on how and when to act, should be better dissected and understood to improve the QoL of the patients. In the present review, we focused on the role of the oncologists, the aesthetic medicine specialists, the dermatologists, radiotherapists, and the nutritionists in supporting the BCP. A MDT assumes a crucial role in the care of and for breast cancer survivors (online suppl. Fig. 1; see www.karger.com/doi/10.1159/000528280 for all online suppl. material). Indeed, “living well means living longer,” so it must be done to improve the prognosis of the cancer patient, allowing us to better investigate the role of the involved specialists in supporting the recovery of the affected patient.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research was funded by “Fondo di Ateneo per la Ricerca 2021 (Margherita Maioli).”

Author Contributions

All authors were involved in project conception and in writing the article. All authors have read and agreed to the published version of the manuscript.

Supplementary Material

Supplementary data

Funding Statement

This research was funded by “Fondo di Ateneo per la Ricerca 2021 (Margherita Maioli).”