Overview of side effects of chemotherapy for early-stage breast cancer

INTRODUCTION — Adjuvant chemotherapy results in an improvement in both disease-free and overall survival and is routinely administered for women with early-stage breast cancer. However, treatment is associated with both acute and long-term complications for the breast cancer survivor. The number, nature, and costs of severe adverse effects experienced by women receiving adjuvant chemotherapy for breast cancer are relatively unknown, but may be more common than suspected from what has been reported from clinical trials.

This was illustrated in a series of 12,239 women aged 63 or younger with newly diagnosed breast cancer between 1998 and 2002, 4075 of whom were treated with adjuvant chemotherapy [1]. Women who were treated with chemotherapy were significantly more likely to visit emergency rooms for all causes (61 versus 42 percent) and for serious adverse effects (16 versus 5 percent). For patients receiving chemotherapy, the major reasons prompting hospitalization or an emergency room visit during the year after their breast cancer diagnosis were:

●Fever or infection

●Neutropenia or thrombocytopenia

●Dehydration or electrolyte disorders

●Nausea, emesis, or diarrhea

●Anemia

●Constitutional symptoms

●Deep venous thrombosis or pulmonary embolus

●Malnutrition

An overview of acute complications of adjuvant chemotherapy is presented here. Long-term complications and the treatment of breast cancer subsets are discussed separately, as are side effects of hormonal treatments and human epidermal growth factor receptor 2-directed agents. Hypersensitivity reactions associated with chemotherapy are also presented elsewhere.

●(See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse".)

●(See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)

●(See "Adjuvant systemic therapy for HER2-positive breast cancer".)

●(See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

●(See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Side effects' and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Side effects'.)

●(See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

●(See "Infusion reactions to systemic chemotherapy".)

SPECIFIC ISSUES RELATED TO INDIVIDUAL AGENTS

Taxanes — Taxanes are used frequently in early-stage breast cancer. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Rationale for anthracycline- and taxane-containing regimen' and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment' and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Choice of chemotherapy'.)

Neurotoxicity — Taxanes such as paclitaxel and docetaxel are associated with both a motor and sensory neuropathy that is dose and schedule dependent and cumulative [2]. For those receiving paclitaxel, grade 2 to 4 neuropathy occurs in 25 to 30 percent of patients, with grade 3 or 4 neuropathy occurring in 5 to 10 percent. For patients receiving docetaxel, grade 2 to 4 neuropathy occurs in 15 to 20 percent, and grade 3 or 4 neuropathy in approximately 5 percent [3]. Early recognition and subsequent treatment delay or dose reduction may alleviate or prevent the worsening of symptoms in most cases. Symptoms usually improve slowly after discontinuation of treatment (over weeks to months); if severe, recovery may be incomplete. In addition, paclitaxel can cause an acute pain syndrome in the first few days after administration, characterized by a diffuse aching discomfort that predominantly impacts the legs, hips, and back, though some patients may complain of more widespread pain [4]. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Taxanes'.)

Of available agents, duloxetine was shown to be effective in the treatment of chemotherapy-induced neuropathy. Other options including gabapentin or a tricyclic antidepressant have not demonstrated clear benefit, but in the setting of limited options a therapeutic trial may be appropriate. These results are reviewed elsewhere. Dose reductions and dose holds are recommended for patients with cumulative symptom burden with functional deficits [5]. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Treatment'.)

Paclitaxel is associated with transient scintillating scotomas during infusion in approximately 20 percent of patients, which are typically self-limited. (See "Ocular side effects of systemically administered chemotherapy".)

Pulmonary toxicity — Paclitaxel and docetaxel are associated with pneumonitis in approximately 5 percent or less of patients. Concurrent administration of taxanes with checkpoint inhibitor therapy in early-stage breast cancer can be further associated with a higher risk of pulmonary toxicity [6]. Presentation is typically with dyspnea, cough, malaise, and/or low-grade fever. Nonspecific features of pneumonitis are typically seen on imaging. Although most cases are self-limited and resolve with discontinuation of taxane therapy, glucocorticoids are indicated in cases of severe pneumonitis. Further discussion of specific indications is found elsewhere. (See "Taxane-induced pulmonary toxicity", section on 'Treatment'.)

Hepatotoxicity — Hepatotoxicity may be seen in up to one-third of patients receiving taxanes (more commonly paclitaxel) [7], with higher incidence among those receiving concurrent immunotherapy [6]. For example, one study of patients receiving paclitaxel reported elevations in bilirubin in 8 percent, alkaline phosphatase in 23 percent, aspartate transaminase in 16 percent, and alanine transaminase in 33 percent [8]. It is typically mild, and in such cases, no interventions are required, although dose adjustments may be necessary. For more severe cases, discontinuation may be indicated. Given that both paclitaxel and docetaxel are excreted by the liver, liver function abnormalities may increase nonhepatic toxicities, though no evidence suggests impaired efficacy of the agents. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Combination chemotherapy regimens'.)

Musculoskeletal side effects — Dose-related myalgias and arthralgias are a particular problem with paclitaxel; they typically develop between 72 and 96 hours of treatment and are much less common with weekly compared with every-three-week regimens [9]. The pathophysiologic mechanism is unknown; however, accumulating evidence supports the view that this is a manifestation of acute neurotoxicity (it is referred to as paclitaxel-associated acute pain syndrome) [4]. The onset of symptoms is associated with individual doses and does not appear to be a cumulative effect [10]. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Clinical features, incidence, and risk factors'.)

There is a paucity of data on prevention and treatment of this complication, but options for management include the use of nonsteroidal anti-inflammatory drugs, gabapentin, glutamine, and antihistamines [10].

Anthracyclines — Anthracyclines are used frequently in early breast cancer. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Anthracycline-based therapy' and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Rationale for anthracycline- and taxane-containing regimen'.)

In the acute setting, anthracycline-containing regimens are associated with higher frequency of emesis relative to non-anthracycline-containing regimens, though rates are lower than historically due to newer antiemetics. Anthracyclines are also associated with mucositis, hand-foot syndrome, neutropenia, anemia, and complete alopecia. (See 'Mucositis' below and 'Dermatologic toxicity' below and 'Myelosuppression' below.)

A small number of patients may experience acute cardiotoxicity. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Long-term side effects include a small but higher incidence of cardiotoxicity and secondary malignancies relative to non-anthracycline-containing regimens.

Capecitabine — Adjuvant therapy with capecitabine is currently indicated in patients with high-risk, triple-negative breast cancer with residual disease after neoadjuvant chemotherapy [11]. Most common toxicities include fatigue, nausea, and diarrhea. Approximately two-thirds of patients receiving adjuvant capecitabine will experience hand-foot syndrome (pain, erythema, and/or blistering on the palms of the hands and soles of the feet) [11]. These are typically managed with standard symptom management strategies as well as dose reductions, which are very common with this regimen. Management of these toxicities is discussed elsewhere. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Capecitabine' and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Capecitabine' and "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

This agent is now commonly combined with immunotherapy, such as pembrolizumab, which can be associated with additional immune-mediated toxicities. (See "Toxicities associated with immune checkpoint inhibitors".)

Carboplatin — Several regimens in early-stage breast cancer utilize carboplatin. These include:

●Docetaxel and carboplatin [12,13]

●Docetaxel, carboplatin, pertuzumab, and trastuzumab

●Paclitaxel, carboplatin, and pembrolizumab [14]

The most common toxicities include fatigue, cytopenias, and nausea. Neuropathy and nephrotoxicity are less common. Management of toxicities associated with platinum agents if found elsewhere. (See "Prevention of chemotherapy-induced nausea and vomiting in adults" and "Overview of neurologic complications of platinum-based chemotherapy" and "Nephrotoxicity of chemotherapy and other cytotoxic agents".)

Cyclophosphamide — In early-stage breast cancer, cyclophosphamide is used in combination with anthracyclines, taxanes, and 5-fluorouracil. At the doses used in these regimens, the most common toxicities are nausea, cytopenia, ovarian insufficiency, and fatigue. Late toxicities can include a small risk of secondary hematologic malignancies. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Cyclophosphamide pulmonary toxicity" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Cyclophosphamide'.)

GENERAL ISSUES RELATED TO CHEMOTHERAPY

Myelosuppression

Neutropenia — Most patients receiving combination chemotherapy experience a small to moderate reduction in the white blood cell count, 10 to 14 days after each cycle. It usually resolves prior to the next course of chemotherapy. However, if severe or prolonged, it can result in fever or life-threatening infection.

For most regimens used in breast cancer therapy, the risk of febrile neutropenia is less than 2 percent. However, there are several regimens associated with at least a 20 percent risk of neutropenia:

●Docetaxel-containing regimens (both TAC [docetaxel, doxorubicin, cyclophosphamide] and TC [docetaxel, cyclophosphamide])

●Treatment every two weeks (ie, dose-dense, eg, ACT [doxorubicin, cyclophosphamide, docetaxel])

●Docetaxel carboplatin-based regimen with or without HER2-targeted therapies (pertuzumab and trastuzumab)

Patients receiving either docetaxel-containing regimens or dose-dense chemotherapy regimens, and those who experienced neutropenic fever with their previously administered cycle, are treated with granulocyte colony stimulating factors (G-CSF) to reduce the duration of neutropenia and the risk of neutropenic fever [15,16]. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Primary prophylaxis' and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Secondary prophylaxis'.)

Anemia — A common side effect of chemotherapy is myelosuppression, including the onset of anemia. Anemia can impair a patient's functional status, diminish physiologic reserve, and result in significant fatigue.

While erythropoietin-stimulating agents (ESAs) are available for the treatment of anemia, their administration has been associated with increased risks for thromboembolic events and worse clinical outcomes, including survival. For women with early-stage breast cancer receiving chemotherapy with curative intent, we do not administer ESAs. Rather, for patients with a symptomatic anemia, we offer red blood cell transfusions, as discussed elsewhere. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Effect on disease control and survival'.)

Gastrointestinal side effects

Nausea and vomiting — Although significant progress has been made, chemotherapy-induced nausea and vomiting remains an important adverse effect of treatment. The dose-dense combination of doxorubicin and cyclophosphamide is considered highly emetogenic (experienced by >90 percent of patients) [17], whereas regimens containing either docetaxel, paclitaxel, or carboplatin are moderately emetogenic (experienced by 60 to 90 percent of patients). All patients receiving adjuvant chemotherapy require antiemetic therapy tailored to the risk of the specific treatment regimen [18]. Details of treatment are found elsewhere. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

Mucositis — Patients at risk for mucositis and those who experienced mucositis with a prior cycle should receive oral cryotherapy (ice chips swished around the mouth for 30 minutes) around the time of drug administration. A variety of mucosal coating agents are available, including topical diphenhydramine, oral antacids, lidocaine, and compounded mixtures, such as "miracle mouthwash," that combine such agents. Although data are lacking to support one of these agents over another, a therapeutic trial of any of these options is reasonable. The use of systemic antifungal therapy (ie, nystatin suspension or fluconazole) is not recommended. Further discussion is found elsewhere. (See "Oral toxicity associated with systemic anticancer therapy".)

Oral mucositis is the inflammation of the buccal mucosa or soft palate. It typically begins as a burning sensation in the mouth, but as it increases in severity, it can result in ulceration with an inability to eat or drink. Fortunately, the frequency of severe oropharyngeal mucositis or stomatitis and of diarrhea requiring intravenous-fluid therapy or hospitalization is low for regimens of cyclophosphamide and doxorubicin, largely because of the widespread use of G-CSF to prevent neutropenia. However, incidence of severe mucositis but may be higher when the regimen also includes fluorouracil (eg, cyclophosphamide, doxorubicin, and fluorouracil [CAF]) [2]. Higher risk of stomatitis or diarrhea is evident in multi-agent chemotherapy immunotherapy combination regimens [14].

Weight gain — Up to 96 percent of women gain weight during treatment, and this appears to be particularly problematic among premenopausal women [19]. Potential mechanisms may involve energy imbalances provoked by chemotherapy, such as poor treatment tolerance, hormonal alterations, and changes in adiposity that may induce insulin resistance [20].

Because obesity has been associated with inferior outcomes in women treated for breast cancer, all patients receiving chemotherapy should meet with a nutritionist about diet and exercise programs during and after completion of chemotherapy [21-23].

Dermatologic toxicity

Cutaneous side effects — Most patients tolerate adjuvant chemotherapy for breast cancer without notable dermatologic toxicities, although pigmentary changes caused by anthracyclines and taxanes have been reported. Hand-foot syndrome, associated with capecitabine, is described above. (See 'Capecitabine' above.)

Other toxicities attributed to anthracyclines and docetaxel have been described, including nail changes such as discoloration, brittleness, ridging, and the nail coming off during treatment. In addition, subacute cutaneous lupus erythematosus as well as a variant of acral erythema called fixed erythrodysesthesia plaque occurring proximal to the infusion site can occur. (See "Cutaneous adverse effects of conventional chemotherapy agents".)

Alopecia — The agents most commonly used in adjuvant therapy for breast cancer (eg, doxorubicin, cyclophosphamide, docetaxel, and paclitaxel) are all associated with high frequency of alopecia. Therefore, options such as head wraps, hats, or wigs should be discussed in advance in order to prepare the patient for the likely outcome of hair loss.

For women with breast cancer who are receiving chemotherapy that is expected to result in significant alopecia, and who place a high value on avoidance of chemotherapy-induced alopecia, a scalp-cooling device is appropriate. Chemotherapy-induced alopecia and scalp cooling is discussed in detail elsewhere. (See "Alopecia related to systemic cancer therapy" and "Alopecia related to systemic cancer therapy", section on 'Scalp hypothermia (scalp cooling)'.)

Hair thinning typically begins after the second or third cycle of treatment, with more substantial loss as treatment continues. Hair loss is typically transient, and regrowth typically occurs after cessation of therapy, although reduced density may be observed. The rates of alopecia not progressing to needing a hairpiece (wig) are about 75 percent with docetaxel and cyclophosphamide regimen (ie, TC), when scalp cooling is used. By contrast, with anthracycline-containing adjuvant chemotherapy, scalp cooling only prevents about one-half of women from needing a hairpiece due to alopecia. Additionally, the success of scalp cooling can be variable based on the ethnicity profile of the hair [24,25]. Although a scalp-cooling device is sanctioned by the US Food and Drug Administration, Medicare, Medicaid, and third-party payers do not universally cover the costs of this scalp-cooling device or other methods of scalp cooling, although depending on the coverage plan, some insurance coverage has been available to some patients.

Fatigue — Moderate to severe fatigue is a common complaint during adjuvant chemotherapy [26-28]. Possible contributory factors include anemia and vasomotor symptoms that lead to sleep disturbance and depression [29]. For most patients, fatigue generally resolves following the completion of treatment [30]. However, some patients with early-stage breast cancer may have persistent fatigue symptoms after completion of treatment [31]. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment".)

Treatment of fatigue during therapy should begin with an evaluation for potentially correctable etiologic factors, including anemia, pain, depression, hypoxia, or fluid/electrolyte imbalances. In many cases, fatigue will not be attributable to a correctable condition, and treatment should be directed towards symptomatic relief. (See "Cancer-related fatigue: Treatment".)

Sexual and reproductive side effects

Vasomotor symptoms — Vasomotor symptoms may develop because of premature cessation of ovarian function caused by the administration of adjuvant chemotherapy, or for those with hormone receptor-positive tumors, the use of adjuvant hormone therapy (tamoxifen, anastrozole, oophorectomy, gonadotropin-releasing hormone [GnRH] agonists). (See 'Chemotherapy-induced amenorrhea' below.)

The major clinical manifestations of vasomotor symptoms are hot flashes, sleep disturbance, headache, and irritability. The use of systemic estrogen replacement is generally prohibited because data from randomized trials suggest that estrogen therapy may be associated with excessive risk. Therefore, we recommend the use of non-estrogen therapies for controlling symptoms before considering estrogen therapy in these women. This is consistent with guidelines from the North American Menopause Society [32]. The risks of postmenopausal hormonal therapy in women with a prior history of breast cancer are covered separately. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Personal history of breast cancer'.)

Several non-estrogenic treatments such as gabapentin and the selective serotonin and norepinephrine reuptake inhibitors (SSRIs and SSNRIs, respectively) may provide symptomatic benefit for women with troublesome vasomotor symptoms. For those who will later initiate treatment with tamoxifen, it should be noted that SSRIs and SSNRIs have inhibitory activity on CYP2D6, the liver enzyme that is responsible for converting tamoxifen to its active metabolite endoxifen. Although breast outcomes have not been shown to be worsened for those on other SSRIs or SSNRIs while on tamoxifen, we typically choose an agent with minimal inhibitory activity on CYP2D6 if initiating this type of therapy (eg, venlafaxine). In addition, oxybutynin is another possible option for patients with vasomotor symptoms [33]. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators", section on 'Intrinsic resistance' and "Menopausal hot flashes" and "Menopausal hot flashes", section on 'Women with breast cancer'.)

In addition to pharmacologic treatments, cognitive behavioral therapy (CBT) and exercise may alleviate the burden of vasomotor symptoms. In one trial, 422 women were randomly assigned to CBT, exercise, CBT plus exercise, or to a control group (no interventions) [34]. CBT consisted of six weekly group sessions that incorporated relaxation techniques. The exercise program was a 12-week individualized, home-based program that required 2.5 to 3 hours of activity per week. Of those who participated, 64 percent were ≤3 years out from completion of chemotherapy and 93 percent were still taking adjuvant endocrine therapy. High levels of noncompliance were reported (58, 64, and 70 percent in the CBT, exercise, and CBT plus exercise groups, respectively). When outcomes were analyzed using data from women who were compliant (n = 219), all three interventions resulted in significantly lower endocrine symptoms compared with controls at 12 weeks and 6 months. In addition, CBT with or without exercise significantly reduced the perceived burden associated with hot flashes or night sweats, which was sustained at six months.

The data supporting acupuncture for hot flashes in women with breast cancer have mixed results and further studies are necessary [35,36]. (See "Menopausal hot flashes", section on 'Inconsistent evidence of efficacy'.)

Nevertheless, given lack of harm, it may be considered in breast cancer patients in whom pharmacologic therapy has been ineffective or for those who prefer to avoid taking medication for their hot flashes. However, access to qualified practitioners as well as limited insurance coverage has been challenging [37].

Chemotherapy-induced amenorrhea — Chemotherapy-induced amenorrhea is a well-recognized side effect of cytotoxic chemotherapy. These drugs appear to have a greater effect on follicular development than on oocytes, with variable degrees of subsequent ovarian dysfunction. Some women develop complete follicular depletion and permanent ovarian failure during chemotherapy, while others become temporarily amenorrheic during therapy, with subsequent return of ovarian function, menstrual cycles, and fertility months to years after treatment cessation. (See "Overview of infertility and pregnancy outcome in cancer survivors".)

Amenorrhea is a poor surrogate for ovarian function and should not be considered as proof of menopause. For those with hormone receptor-positive disease, determining whether a patient is menopausal (versus amenorrheic, but not menopausal) after chemotherapy is an important issue, given that menopausal status influences the choice of endocrine therapy. This is discussed elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Indications' and "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer", section on 'Transitioning from tamoxifen to an AI after menopause' and "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer", section on 'Definition of menopause'.)

Risk factors — There are well-recognized risk factors for chemotherapy-induced amenorrhea or ovarian failure, such as age, chemotherapy regimen, subsequent use of endocrine therapy, and genetics. These are discussed below.

●Age – The risk of amenorrhea is greater in women who are over the age of 40 at the time of treatment initiation (table 1) [38-40]. In addition, ovarian failure is less often reversible in older women [2,40,41]. This was illustrated in a combined analysis of three trials of women (n = 796) treated with adjuvant doxorubicin-containing chemotherapy [42]:

•Women under 30 years did not experience chemotherapy-induced amenorrhea.

•Chemotherapy-induced amenorrhea occurred in 96 percent of women age 40 to 49 years.

•Ovarian function (evidenced by resumption of menses) returned in 50 percent of women younger than 40 years, but only in 10 percent of women over 40 years.

●Chemotherapy regimen – The incidence of chemotherapy-induced ovarian failure differs with the type of chemotherapy regimen. In a study evaluating amenorrhea following adjuvant chemotherapy in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B30 trial, the rates of prolonged amenorrhea (≥6 months) were lowest in the group treated with a regimen that did not contain cyclophosphamide (38 percent) and highest in those receiving a cyclophosphamide-containing treatment (70 percent) [43].

In general, rates of both transient and prolonged amenorrhea are higher with CMF or CEF/CAF-type regimens as compared with AC (table 1) [38,39,44]. Although some trials evaluating the addition of taxanes report higher rates of prolonged amenorrhea than expected with AC alone, others suggest that rates are similar or even lower [45-51].

The relative intensity of the chemotherapy regimen, including higher doses, longer duration, and the use of multi-agent regimens, confers higher rates of amenorrhea [52]. However, the impact of dose-dense therapy on rates of amenorrhea has not been well studied. The available data come from one prospective study of FEC administered on an every 14 or 21-day basis [53]. The incidence of amenorrhea was identical in both arms (64 percent). (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Importance of chemotherapy schedule'.)

Data are limited on the impact of newer targeted therapies and immunotherapies on ovarian function, although there is some evidence for detrimental impact on ovarian function [54].

●Genetic factors – Inherited genetic factors may play a role in determining which women will develop chemotherapy-induced amenorrhea or ovarian failure. Although not well studied, it is possible that genetic changes that have been associated with spontaneous premature menopause might also predict this complication [55]. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

One category of candidate genes includes those involved in drug transport and metabolism [56]. CYP2C19 is an enzyme of the cytochrome P450 family that is involved in the metabolism of many drugs, including cyclophosphamide. Although prospective studies have not been carried out, individuals receiving single-agent cyclophosphamide for lupus nephritis, who are homozygous or heterozygous for a CYP2C19 variant (CYP2C19*2), had a lower risk of ovarian failure (relative risk 0.10, 95% CI 0.02-0.52) after adjustment for age and total number of cyclophosphamide pulses [56]. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Gonadal toxicity'.)

Menopausal symptoms — Hot flashes, vaginal dryness, dyspareunia, depression, and sleep disturbance are often reported by postmenopausal women with breast cancer and can result in disruptions in quality of life during adjuvant therapy [57,58]. Successful management includes careful symptom assessment, education, counseling, and behavioral or pharmacologic interventions [58]. The treatment of menopausal symptoms is similar to the treatment of vasomotor symptoms, which is discussed above. (See 'Vasomotor symptoms' above.)

Management of vaginal dryness, including risks and benefits of topical estrogen therapy, is discussed elsewhere. (See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse", section on 'Sexual dysfunction'.)

Infertility — Breast cancer survivors have a lower rate of subsequent pregnancy than the general population. (See "Overview of infertility and pregnancy outcome in cancer survivors".)

Because chemotherapy-induced amenorrhea is often transient and reversible (up to 24 months post-treatment), especially in younger women, sexually active women should be prescribed nonhormonal methods of birth control even if they are not menstruating because they may still ovulate and become pregnant. (See "Approach to the patient following treatment for breast cancer", section on 'Contraception after breast cancer'.)

Although administration of GnRH agonists has been studied as a way to prevent damage to ovarian tissue for patients undergoing chemotherapy, this issue is controversial and discussed in detail elsewhere. GnRH agonists may be offered to patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency but should not be used in place of proven fertility preservation methods. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Breast cancer'.)

Although women may experience the return of menstrual cycles after cessation of chemotherapy, this is not a good marker of normal ovarian function [59]. For women who are concerned about fertility during and after chemotherapy, testing for ovarian reserve is available. Serum measurement of anti-Müllerian hormone and inhibin B were found to correlate with chemotherapy-induced amenorrhea in a study of 127 patients [60]. However, data on the association of anti-müllerian hormones with future fertility outcomes after cancer treatment were limited [61].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Breast cancer guide to diagnosis and treatment (Beyond the Basics)" and "Patient education: Treatment of early HER2-positive breast cancer (Beyond the Basics)")

SUMMARY

●Introduction – Adjuvant chemotherapy represents a significant advance in the management of early-stage breast cancer, resulting in many lives being saved. Although the acute toxicities must be considered when assessing the relative risk-benefit ratio of adjuvant chemotherapy, in general, the survival benefit gained exceeds the negative impact of side effects on quality of life in both premenopausal and postmenopausal women. (See 'Introduction' above.)

●Issues related to specific agents

•Taxanes – Taxanes, such as paclitaxel, are associated with both a motor and sensory neuropathy that is dose- and schedule-dependent and cumulative. Taxanes are also associated with pneumonitis in a minority of cases, as well as dose-related myalgias and arthralgias. (See 'Taxanes' above.)

•Anthracyclines – Anthracycline-containing regimens are associated with higher frequency of emesis relative to non-anthracycline-containing regimens, though rates are lower than historically due to newer antiemetics. Anthracyclines are also associated with mucositis, hand-foot syndrome, neutropenia, anemia, and complete alopecia. A small number of patients may experience acute cardiotoxicity. (See 'Anthracyclines' above.)

•Capecitabine – Most common toxicities include fatigue, nausea, and diarrhea. Approximately two-thirds of patients receiving adjuvant capecitabine will experience hand-foot syndrome. (See 'Capecitabine' above.)

•Carboplatin – The most common toxicities include fatigue, cytopenias, and nausea. (See 'Carboplatin' above.)

•Cyclophosphamide – The most common toxicities are nausea, cytopenia, ovarian insufficiency, and fatigue. Late toxicities can include a small risk of secondary hematologic malignancies. (See 'Cyclophosphamide' above.)

●General issues related to chemotherapy

•Nausea, vomiting, stomatitis (mucositis), and bone marrow suppression are acute and reversible side effects of systemic chemotherapy. (See 'Gastrointestinal side effects' above and 'Myelosuppression' above.)

•The agents most commonly used in adjuvant therapy for breast cancer are associated with a high frequency of alopecia. Hair loss is typically transient, and regrowth typically occurs after cessation of therapy, although reduced density may be observed. Chemotherapy-induced alopecia and scalp cooling is discussed in detail elsewhere. (See "Alopecia related to systemic cancer therapy" and "Alopecia related to systemic cancer therapy", section on 'Scalp hypothermia (scalp cooling)'.)

•Moderate to severe fatigue is a common complaint during adjuvant chemotherapy; contributory factors include anemia, vasomotor symptoms, and depression. (See 'Fatigue' above.)

•Vasomotor symptoms may develop because of premature cessation of ovarian function caused by the administration of adjuvant chemotherapy or the use of adjuvant hormone therapy in women with hormone receptor-positive tumors. (See 'Vasomotor symptoms' above.)

•Chemotherapy-induced amenorrhea is a well-recognized side effect of cytotoxic chemotherapy. The frequency and duration vary according to age, the specific chemotherapy regimen, and use of endocrine therapy. The consequences of premature ovarian failure include menopausal symptoms and bone loss. (See 'Chemotherapy-induced amenorrhea' above.)