July 23, 2024

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Long-term Complications and Management of Adjuvant Therapy for Breast Cancer

Long-term Complications and Management of Adjuvant Therapy for Breast Cancer

Long-term Complications and Management of Adjuvant Therapy for Breast Cancer

Breast cancer is one of the most common malignant tumors, accounting for approximately one-fourth of all malignant tumor cases globally.

With the development of precision medicine, chemotherapy, targeted therapy, endocrine therapy, and immunotherapy have become crucial components of comprehensive breast cancer treatment.

While these treatments lead to effective therapy and long-term survival for many breast cancer patients, they also bring about various long-term or permanent complications, significantly impacting their quality of life.

Recently, the British Medical Journal published a review titled “Advances in the care of breast cancer survivors,” providing a systematic overview of long-term complications associated with breast cancer treatment.

This article is based on that review and aims to summarize the long-term complications and management of adjuvant therapies, including chemotherapy, targeted therapy, endocrine therapy, and immunotherapy.

Long-term Complications and Management of Adjuvant Therapy for Breast Cancer

Chemotherapy-Related Complications:

Chemotherapy for breast cancer primarily involves three classes of drugs: anthracyclines, taxanes, and alkylating agents. These traditional chemotherapy drugs have been used for decades, and their toxic characteristics are now well-understood.

  • Anthracyclines: These drugs may increase the risk of cardiovascular events, such as arrhythmias and heart failure. Long-term irreversible complications include chronic dilated cardiomyopathy. Currently, dexrazoxane is widely recognized as the primary drug to prevent anthracycline-induced cardiac toxicity. The use of anthracyclines also carries risks of secondary leukemia, reproductive dysfunction affecting fertility, worsening menopausal symptoms, and potential skeletal toxicity.

  • Taxanes: Taxane drugs can lead to peripheral neuropathy, primarily affecting the sensory peripheral nerves of the hands and feet, presenting as a stocking-and-glove distribution. Duloxetine has shown potential in relieving taxane-induced neuropathy, but effective prevention or treatment methods for numbness and tingling are still lacking.

  • Alkylating Agents: Cyclophosphamide, the most commonly used alkylating agent, increases the risk of secondary leukemia, reproductive dysfunction affecting fertility, worsening menopausal symptoms, and potential skeletal toxicity. Currently, there are no effective preventive or treatment methods.

  • Capecitabine and Platinum-based Drugs: While the use of capecitabine and platinum-based drugs in breast cancer is relatively short-term, studies suggest potential impacts on ovarian function and an increased risk of secondary leukemia in ovarian cancer patients.

Targeted Therapy-Related Complications:

Targeted therapy for breast cancer includes HER2-targeted therapy and treatment against BRCA1/2, CDK4/6, and PD-1/PD-L1. Although targeted drugs have fewer side effects than traditional chemotherapy drugs, their long-term toxicity evolves into subacute and chronic forms due to the extended treatment duration.

  • Anti-HER2 Targeted Therapy: Drugs like trastuzumab, pertuzumab, ado-trastuzumab emtansine (T-DM1), and neratinib are associated with varying degrees of cardiac toxicity, liver toxicity, and the risk of persistent neuropathy.

  • PARP Inhibitors: PARP inhibitors, such as olaparib, are mainly used in breast cancer patients with BRCA1/2 mutations. Chronic and late toxicity data are mostly derived from ovarian cancer patients, showing potential for severe acute myeloid leukemia/myelodysplastic syndrome due to interference with DNA repair pathways.

  • CDK4/6 Inhibitors: While interstitial lung disease caused by abemaciclib is rare, it poses a lethal risk, requiring treatment with prednisolone if it occurs.

  • PD-1/PD-L1 Inhibitors: Immune checkpoint inhibitors like pembrolizumab and atezolizumab, recently approved for breast cancer, lack comprehensive long-term complication data. Around 43.2% of patients may experience long-term mild to severe immune-related adverse effects, including mild hypothyroidism (14.0%) and potentially lifelong treatment with hydrocortisone in case of severe pituitary inflammation (2.1%).

Endocrine Therapy-Related Complications:

Endocrine therapy for breast cancer includes various medications, such as tamoxifen and aromatase inhibitors (letrozole, anastrozole, and exemestane), as well as gonadotropin-releasing hormone agonists (GnRH-a) like goserelin and leuprorelin. For early-stage breast cancer patients, endocrine therapy may continue for up to 10 years, warranting careful consideration of its long-term toxic complications, particularly in premenopausal patients using GnRH-a to suppress ovarian function.

  • Vasomotor Dysfunction: Characterized by hot flashes and night sweats, this common symptom of menopause occurs in up to 80% of patients undergoing endocrine therapy. Paroxetine and megestrol acetate are effective drugs for treating hot flashes, but they may interact with tamoxifen, reducing its efficacy.

  • Postmenopausal Genitourinary Syndrome: Common in patients receiving aromatase inhibitors and ovarian suppression, this syndrome is related to low estrogen levels, manifesting as vaginal dryness, sexual difficulties, and reduced libido. In patients without a history of breast cancer, estrogen injections into the vagina can effectively treat vaginal dryness. However, in patients with estrogen-sensitive breast cancer history, this approach may pose some risks.

  • Musculoskeletal Symptoms: Aromatase inhibitors commonly cause musculoskeletal symptoms, including muscle, bone, and joint pain. Duloxetine can be used to treat widespread chronic pain.

  • Hair Loss: Over one-third of patients undergoing endocrine therapy experience hair thinning and loss. Minoxidil, a vasodilator, effectively promotes hair follicle growth, providing a viable treatment for endocrine therapy-related hair loss.

  • Osteoporosis: Aromatase inhibitors increase the risk of osteoporosis and fractures. Bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors can reduce the risk of bone loss and fractures in postmenopausal and premenopausal patients with ovarian function suppression or chemotherapy-induced ovarian failure.


In conclusion, the overall occurrence of long-term complications related to adjuvant therapy for breast cancer is relatively low.

However, addressing these complications and finding effective preventive and treatment methods remains challenging.

Conditions such as peripheral neuropathy, hair loss, and vaginal dryness lack definitive treatment options. Further research is needed to determine the optimal treatment strategies, avoiding ineffective treatments or related toxic side effects.

With ongoing developments in medical technology, we anticipate significant improvements in the prognosis and quality of life for breast cancer patients.

Long-term Complications and Management of Adjuvant Therapy for Breast Cancer


Cathcart-Rake EJ, Tevaarwerk AJ, Haddad TC, D’Andre SD, Ruddy KJ. Advances in the care of breast cancer survivors. BMJ. 2023 Sep 18;382:e071565.

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