Lancet Oncology: European Consensus on Radiotherapy Combined with Novel Drugs for Breast Cancer

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Lancet Oncology: European Consensus on Radiotherapy Combined with Novel Drugs for Breast Cancer

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Lancet Oncology: European Consensus on Radiotherapy Combined with Novel Drugs for Breast Cancer

Over the past 15 years, the rapid development of novel anti-cancer drugs has disrupted traditional treatment paradigms for breast cancer, now becoming standard therapy.

Local treatments, such as radiotherapy, play a crucial role in breast cancer management. The challenge lies in effectively and safely combining novel anti-cancer drugs with local treatments.

In response, the European Society for Radiotherapy and Oncology (ESTRO) conducted a comprehensive assessment of the evidence-based medicine on combining novel anti-cancer drugs with radiotherapy for breast cancer treatment.

They formulated a consensus guideline on radiotherapy combined with novel anti-cancer drug treatment for breast cancer, published in the February 2024 issue of The Lancet Oncology.

The guideline was developed by a multidisciplinary committee consisting of a core group, expert groups from various oncology fields, a patient advocate, and a representative from the ESTRO guideline committee.

The core group initially established the direction and methodology of the research, and evaluated key or systematic literature reviews.

The core group and expert groups jointly reviewed the literature, evaluated the key or systematic literature reviews, and proposed preliminary drafting opinions.

The core group and expert groups conducted two rounds of anonymous voting through web conferences.

The core group and expert groups made initial presentations at the ESTRO annual meeting, followed by open discussions and approval of the consensus, leading to the final draft.

Consensus: Key Issues and Recommendations

Key Issue 1: Minimum Requirements for Radiotherapy Parameters in Clinical Studies of Novel Anti-Cancer Drug Treatment for Breast Cancer

Consensus 1a:

Long-term safety data for the combination of novel anti-cancer drugs and radiotherapy in early-stage breast cancer are required (Evidence Level V, Recommendation Level A; Strong Consensus 95%).

Consensus 1b:

Safety results of clinical studies on the combination of novel anti-cancer drugs and radiotherapy in early and late-stage breast cancer should report radiotherapy parameters and toxicity (Evidence Level V, Recommendation Level A; Unanimous Agreement 100%).

Consensus 1c:

There is currently no high-quality clinical research data on the combination of novel anti-cancer drugs and radiotherapy in the field of breast cancer. It is strongly recommended to prospectively study existing combination regimens (Evidence Level V, Recommendation Level A; Unanimous Agreement 100%).

Consensus 1d:

Before initiating combined treatment with novel anti-cancer drugs and radiotherapy, full communication with the patient is essential to inform them of potential risks, benefits, and uncertainties (Evidence Level V, Recommendation Level A; Unanimous Agreement 100%).

Discussion:

Radiotherapy is an important adjunctive treatment for breast-conserving therapy for breast cancer, with stereotactic body radiotherapy (SBRT) widely used in patients with brain metastases. In early treatment, it is necessary to determine whether radiotherapy should be administered concurrently or sequentially with each drug or strategy, exploring the potential advantages and disadvantages of each method as a pre-planned exploratory endpoint.

For palliative treatment of advanced breast cancer, different types of toxicity may occur when used in combination with radiotherapy, leading to the suspension of systemic treatment during radiotherapy. Therefore, when considering the combination of novel anti-cancer drugs and radiotherapy, it is important to prioritize the accurate recording of radiotherapy, including the precise delineation of target volumes, and to report radiotherapy plans and outcomes in a clear, internationally recognized format.

Key Issue 2: Safety of Local Treatment Combined with Novel Anti-Cancer Drugs for Breast Cancer Based on Current Evidence-Based Medicine

Consensus 1: CDK4/6 Inhibitors

1a: The combination of CDK4/6 inhibitors and local radiotherapy for adjuvant treatment of breast cancer should only be used in clinical trials or prospective registry cohorts (Evidence Level V, Recommendation Level A; Unanimous Agreement 100%).

1b: The combination of CDK4/6 inhibitors with whole-brain radiotherapy or stereotactic radiosurgery should be studied in clinical trials or prospective registry cohorts (Evidence Level IV, Recommendation Level A; Strong Consensus 92.5%).

1c: For palliative radiotherapy for advanced breast cancer, CDK4/6 inhibitors can be combined with radiotherapy (Evidence Level IV, Recommendation Level B; Strong Consensus 90%).

Discussion: CDK4/6 inhibitors play an important role in the adjuvant treatment and palliative treatment of hormone receptor-positive breast cancer. However, most of the relevant prospective Phase III clinical studies did not find information on the synchronized radiotherapy patient group. Only the PALOMA study specifically studied the combination of palliative radiotherapy with CDK4/6 inhibitors, which suggested temporarily discontinuing palbociclib 7 days before radiotherapy.

Meta-analyses of small-sample clinical studies have found an increase in hematological toxicity with combination therapy but no increase in the incidence of interstitial pneumonia, indicating overall tolerability. The European Organization for Research and Treatment of Cancer (EORTC) recommends that stereotactic ablative radiotherapy (SABR) can be combined with normal doses and frequencies of CDK4/6 inhibitors during treatment.

Consensus 2: PIK3 Inhibitors

2a: The combination of PIK3 inhibitors and radiotherapy is not recommended (Evidence Level V, Recommendation Level D; Strong Consensus 90%).

Discussion: There is currently insufficient evidence to support the safety of combining PI3K-AKT inhibitors with radiotherapy. Further research is needed to determine the optimal doses of these drugs in combination with radiotherapy to maximize tumor response while minimizing toxicity.

Consensus 3: mTOR Inhibitors

3a: The combination of mTOR inhibitors and radiotherapy is not recommended (Evidence Level V, Recommendation Level C; Strong Consensus 95%).

Discussion: There is currently insufficient evidence to support the safety of combining radiotherapy with mTOR inhibitors. Therefore, it is recommended to use radiotherapy and mTOR inhibitors separately.

Consensus 4: HER-2 Targeted Drugs (Non-Antibody Conjugates)

4a: Local radiotherapy for breast cancer can be combined with concurrent trastuzumab ± pertuzumab targeted therapy (Evidence Level I, Recommendation Level A; Unanimous Agreement 100%).

4b: Whole-brain radiotherapy or stereotactic radiosurgery can be combined with concurrent trastuzumab ± pertuzumab targeted therapy (Evidence Level IV, Recommendation Level B; Strong Consensus 97.5%).

4c: Local radiotherapy for breast cancer can be combined with concurrent lapatinib targeted therapy (Evidence Level II, Recommendation Level B; Consensus 85%).

4d: Whole-brain radiotherapy or stereotactic radiosurgery can be combined with concurrent lapatinib targeted therapy (Evidence Level II, Recommendation Level B; Consensus 87.5%).

4e: Other novel TKI targeted drugs (neratinib, tucatinib) combined with radiotherapy should be studied in clinical trials or prospective registry cohorts (Evidence Level V, Recommendation Level C; Strong Consensus 97.5%).

Discussion: Clinical studies have shown that the combination of trastuzumab with postoperative radiotherapy has good tolerability, with no significant increase in acute or late cardiac toxicity and a minimal and reversible incidence of acute skin and esophageal side effects.

Although the combination of pertuzumab with trastuzumab did not specifically analyze adverse reactions to combined radiotherapy, no reports or warnings of increased cardiac toxicity were found. For patients receiving brain radiotherapy/stereotactic radiosurgery, the safety of concurrent dual-target therapy appears acceptable.

The consensus reached by the European Organization for Research and Treatment of Cancer (EORTC) suggests that trastuzumab ± pertuzumab can be used concurrently with radiotherapy without the need to reduce doses.

In clinical studies of lapatinib combined with local radiotherapy, an increase in skin adverse reactions was observed in the lapatinib group, most likely due to lapatinib-related adverse reactions. A meta-analysis of lapatinib combined with stereotactic radiosurgery found that the combination can improve local control rates and survival rates, while reducing the risk of radiation-induced necrosis. There is very little evidence in evidence-based medicine for the combination of other TKIs with radiotherapy.

Consensus 5: HER-2 Antibody Conjugates (ADCs)

5a: Local radiotherapy for breast cancer can be combined with concurrent ado-trastuzumab emtansine (T-DM1) targeted therapy (Evidence Level II, Recommendation Level B; Strong Consensus 92.5%).

5b: Whole-brain radiotherapy or stereotactic radiosurgery is not recommended to be combined with concurrent ado-trastuzumab emtansine (T-DM1) targeted therapy (Evidence Level IV, Recommendation Level D; Strong Consensus 90%).

5c: Other novel antibody-drug conjugates (trastuzumab deruxtecan T-DXd) combined with radiotherapy should be studied in clinical trials or prospective registry cohorts (Evidence Level V, Recommendation Level C; Unanimous Agreement 100%).

Discussion: The Phase III clinical trials of ado-trastuzumab emtansine (T-DM1) included patients undergoing adjuvant breast radiotherapy, but did not report specific radiotherapy-related toxic reactions, nor did they observe significant pulmonary toxic reactions, suggesting that the use of T-DM1 during adjuvant breast radiotherapy is relatively safe. Compared with whole-brain radiotherapy, the combination of T-DM1 with stereotactic radiosurgery significantly increases the risk of symptomatic radiation necrosis in later stages, but there is currently insufficient evidence to assess the safety of concurrent whole-brain radiotherapy/cranial palliative radiotherapy/stereotactic radiosurgery with T-DM1.

Clinical studies of trastuzumab deruxtecan (T-DXd) did not report adverse events related to concurrent radiotherapy, including an increased risk of interstitial lung disease, indicating a lack of safety data for using T-DXd with radiotherapy.

Consensus 6: PARP Inhibitors

6a: PARP inhibitors combined with concurrent radiotherapy for primary, adjuvant, and metastatic breast cancer should be studied in clinical trials or prospective registry cohorts (Evidence Level II, Recommendation Level A; Strong Consensus 97.5%).

6b: Except in clinical trials, PARP inhibitors are not recommended for use in advanced breast cancer patients in combination with concurrent radiotherapy (Evidence Level II, Recommendation Level D; Consensus 80%).

Discussion: Although there have been no reports of serious acute toxicity associated with the use of PARP inhibitors in combination with radiotherapy to date, the existing data on the combination therapy in breast cancer and the long-term safety data are lacking, and there is almost no evidence to suggest that this combination therapy has significant clinical efficacy. There is also insufficient data on the safety and efficacy of using PARP inhibitors in combination with radiotherapy in other malignant tumors.

Given these factors, the consensus recommends against the simultaneous use of PARP inhibitors with radiotherapy until more comprehensive safety and efficacy data are available for this combination therapy.

Consensus 7: Immunotherapy

7a: Local radiotherapy for breast cancer may be considered for concurrent use with immunotherapy (Evidence Level II, Recommendation Level B; Strong Consensus 95%).

7b: Immunotherapy for advanced breast cancer may be considered for concurrent use with radiotherapy or hyperfractionated stereotactic radiotherapy (Evidence Level II, Recommendation Level B; Strong Consensus 92.5%).

Discussion: Immunotherapy has become an important option for triple-negative breast cancer, used in neoadjuvant therapy and as first-line treatment for tumors positive for programmed death-ligand 1 (PD-L1). Clinical data on the use of breast cancer immunotherapy and radiotherapy are still limited, but the existing small amount of clinical evidence suggests that immunotherapy combined with radiotherapy in breast cancer shows some clinical benefits and good tolerability, without increasing the risk of additional serious adverse events.

Additionally, evidence from other malignant tumors confirms that the combination of radiotherapy and immunotherapy is safe. In the future, we still need to explore patient selection, total dose, and dose per fraction for immunotherapy combined with radiotherapy.

Summary

The consensus emphasizes the need to consider factors when conducting clinical research on the combination of novel anti-cancer drugs and radiotherapy for breast cancer.

For different types of novel anti-cancer drugs, the consensus provides specific recommendations based on existing evidence-based medicine on the combination of these drugs with radiotherapy:

1. CDK4/6 and PARP inhibitors show good safety data when used concurrently with radiotherapy, but further investigation is necessary in clinical trials or prospective cohorts.

2. Caution is advised regarding the safety of PI3K-AKT and mTOR inhibitors, and concurrent use with radiotherapy is not recommended.

3. Antibody-based HER2-targeted drugs and immune checkpoint inhibitors, such as trastuzumab, pertuzumab, and lapatinib, can be safely used concurrently with radiotherapy in both adjuvant and palliative treatment of breast cancer.

4. The safety and efficacy of using newer tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates with radiotherapy still require further research.

Lancet Oncology: European Consensus on Radiotherapy Combined with Novel Drugs for Breast Cancer

references
[1]Meattini I, Becherini C, Caini S, Coles CE, Cortes J, Curigliano G, de Azambuja E, Isacke CM, Harbeck N, Kaidar-Person O, Marangoni E, Offersen BV, Rugo HS, Salvestrini V, Visani L , Morandi A, Lambertini M, Poortmans P, Livi L; Consensus Panellist Group. International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations. Lancet Oncol. 2024 Feb;25(2):e73-e83. doi: 10.1016/S1470-2045(23)00534-X. PMID: 38301705. 23, 41: 1830-1840.

(source:internet, reference only)

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