Postoperative Re-irradiaTion With and Without HYPERthermia, or Surgery Only: Toxicity, Quality of Life and Survival in Patients With Locoregional Recurrent Breast Cancer (RT-HYPE)

In the Netherlands, breast cancer patients with locoregional recurrence (LRR) and intermediate- and high-risk factors are treated with surgery with or without postoperative re-irradiation with or without hyperthermia. Retrospective studies showed that 3-year locoregional control after postoperative re-irradiation with hyperthermia was 68-83%, and severe toxicity in up to 40% of LRR patients. Unfortunately, no prospective (randomized) data are available on clinical outcomes. Consequently, variation exists in hyperthermia-treatment and re-irradiation schedules. Prospective real-world data on oncological outcomes, toxicity and quality of life is highly needed for shared decision-making between patients and professionals. These data will be used in the design of a future randomized trial in high-risk LRR patients.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Hyperthermia; Locoregional Recurrence; Re-irradiation
• Intervention / Treatment: Other: No interventions, patient-reported outcomes (PROMs) and toxicity will be collected in both groups.

Detailed Description

The optimal management of LRR breast cancer is multidisciplinary, and based on various prognostic risk factors and previous treatments. The surgical treatment of local recurrences is salvage mastectomy after previous breast-conserving therapy, or local excision after previous mastectomy. Regional treatment of tumor-positive lymph nodes consists of axillary radiotherapy and/or lymph node dissection. Intermediate- and high-risk LRR patients have an indication for surgery +/- postoperative irradiation to improve locoregional control and disease-free survival. In previously irradiated high-risk LRR patients, postoperative re-irradiation is administered with or without hyperthermia in the Netherlands depending on the treating center and treating professional. In unresectable LRR, primary re-irradiation with hyperthermia is the evidence-based standard of care in high-risk LRR in the Netherlands. Hyperthermia is used to increase the therapeutic efficacy of re-irradiation. The introduction of preoperative systemic therapy in 2010 resulted in more resectable high-risk LRRs. This resulted in an increased number of resectable LRR and indications for postoperative re-irradiation instead of primary re-irradiation, including variation in the use of hyperthermia. There is no evidence-based standard of care regarding the combination of postoperative re-irradiation with or without hyperthermia in high-risk LRR patients. The major problem is that only retrospective data and no prospective (randomized) data is available on oncological outcomes (survival and recurrence) and toxicity following postoperative re-irradiation and hyperthermia. Consequently, there is a high need to assess oncological outcomes and toxicity of postoperative re-irradiation with or without hyperthermia in a randomized controlled trial (RCT). So far, an RCT has not been feasible due to the large variation in postoperative re-irradiation and hyperthermia, and preferences regarding hyperthermia-treatment by professionals. In the RT-HYPE study, the investigators evaluate oncological outcomes, toxicity and quality of life in high-risk LRR patients, including the harmonization of hyperthermia-treatment. The results of the RT-HYPE study are needed for the optimization of the shared decision making (SDM) process on post-operative re-irradiation with or without hyperthermia, between professionals and patients. In addition, these results allow to set-up a future RCT comparing postoperative re-irradiation with and without hyperthermia treatment. During the inclusion of patients since February 2024, we have observed some variation in the treatment of high-risk LRRs between participating centers, which is a result of the SDM-process and variation in clinical practice. Consequently, in some patients postoperative re-irradiation +/- hyperthermia is omitted. Also, in patients with a local chest wall recurrence, surgery is sometimes omitted in case of an excellent response to NAST, limiting local treatment to re-irradiation (+/-hyperthermia) only. Consequently, both surgical and radiotherapy treatments vary in high risk LRR patients. In addition, recently published evidence in primary breast cancer showed that post-mastectomy and/or axillary radiotherapy is not needed in selected patients (SUPREMO, Kunkler et al. NEJM 2025, NSABP B-51/RTOG 1304 Mamounas et al. NEJM 2025). First, the randomized controlled SUPREMO trial evaluated the omission of post mastectomy radiotherapy (PMRT) in breast cancer patients with pT1 2N1, pT3N0, or pT2N0 with grade 3 +/- lymphovascular invasion, treated with mastectomy, axillary dissection and systemic therapy. The median follow-up was 9.6 years. Post-mastectomy radiotherapy did not increase 10-year overall survival (i.e. primary endpoint), which was 81.4% with PMRT and 81.9% without PMRT. Secondary outcomes including 10-yr local (1.1%+PMRT, 4.5% no PMRT) and locoregional recurrence rates (2.7%+PMRT, 4.5% no PMRT), disease-free survival (76.2%+PMRT, 75.5% no PMRT) and distant-metastasis free survival (78.2%+PMRT, 79.2% no PMRT) were comparable in both groups. Second, the randomized controlled NSABP B-51/RTOG 1304 trial evaluated postoperative axillary nodal irradiation (ax RT) in patients with clinical stage T1-3N1 and tumor negative axillary lymph nodes after neoadjuvant systemic therapy, (targeted) axillary dissection and local treatment (i.e. breast-conserving surgery and whole breast irradiation or mastectomy (and no PMRT)). After a median follow-up of 59.5 months, 5-year invasive breast cancer recurrence-free interval (i.e. primary endpoint) was 92.7 (+axillary RT) and 91.8% (no axillary RT). The secondary outcomes were similar in both groups, i.e. 5-yr locoregional recurrence-free (98.9% +ax RT, 98.4% no ax RT), distant recurrence-free survival (93.4%+ax RT), 93.4% no ax RT), disease-free survival (88.3% +ax RT, 88.5% no ax RT). Since the indication for postoperative re-irradiation in high-risk LRR is extrapolated from primary breast cancer, in the absence of evidence in the recurrent setting, it is likely that the group with high-risk LRR treated with surgery without postoperative re-irradiation +/- hyperthermia treatment, will increase. After discussion with the study team and radiation oncologists of participating centers in October 2025, we have decided to include two additional groups that reflect current clinical practice: 1. Patients with high-risk LRR (as described in Section Inclusion Criteria) who do not receive postoperative re-irradiation after salvage mastectomy. 2. Patients with a chest wall recurrence after previous mastectomy (as described in Section Inclusion Criteria) and a clinical/radiological complete response after NAST and treated with re-irradiation (+/- hyperthermia) for any microscopic disease without local excision.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Lisca Wurfbain, MD; Phone Number: +31 6-25414750; Email: l.f.wurfbain@amsterdamumc.nl
• Study Contact Backup: Name: Desiree Van Den Bongard, Dr; Phone Number: +31 6-25414750; Email: h.j.vandenbongard@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam UMC
    • Contact: Lisca Wurfbain, MD; Email: l.f.wurfbain@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Eligible patients with local and/or regional recurrence (LRR), i.e true recurrence or second primary tumor:

1. After previous breast-conserving therapy and LRR with high-risk characteristics* treated with salvage mastectomy after previous mastectomy or salvage mastectomy and postoperative re-irradiation

   +/- hyperthermia treatment. In both groups (neo)-adjuvant treatment

2. After previous mastectomy with a chest wall recurrence treated with local excision with or without NAST and postoperative re irradiation (+/-hyperthermia). If these patients have a complete clinical/radiological response after NAST and no surgery (i.e. local excision) is performed, treatment with re-irradiation (with/without hyperthermia) is indicated. Treatment with regional re-irradiation in case of a regional recurrence after (targeted) axillary dissection is allowed.

Description

Inclusion criteria:

• ≥ 18 years old
• WHO performance scale ≤ 2
• Diagnosed with local +/- regional recurrence (LRR) (i.e. true recurrence or second primary) with high-risk tumor characteristics* and previously treated with postoperative local +/- regional irradiation for primary breast cancer/previous recurrence with an indication for salvage mastectomy with/without postoperative re-irradiation (+/-hyperthermia)** if re-irradiation: including overlap of re-irradiated volume with previous irradiated volume
• Diagnosed with a chest wall recurrence and treated with local excision with/without NAST and postoperative re irradiation with/without hyperthermia. In patients with a clinical/radiological complete response after neoadjuvant systemic treatment, NO surgery and re irradiation (+/- hyperthermia) (since surgery is not possible in this group)
• (Neo-)adjuvant systemic (NAST) treatment is allowed
• Use of PET(FES/FDG)-CT for staging of nodal and disseminated disease
• Oligometastases in lymph nodes in the mediastinum, neck, contralateral axillary/supraclavicular region (up to a maximal number of five) is allowed

• Proficient in Dutch at a level allowing to understand the questionnaires and patient information sheet

  * Definition of high-risk tumor characteristics are:

• (Focal) irradical resection
• All clinical and pathological stages except for low-risk LRR: - rcT1-2N0 - r(y)pT1-2N0 ** according to local clinical practice and/or shared decision making process

Exclusion criteria:

• Diagnosed with primary breast sarcoma

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Postoperative re-irradiation with hyperthermia; Postoperative re-irradiation with hyperthermia in patients with locoregional recurrent breast cancer	Other: No interventions, patient-reported outcomes (PROMs) and toxicity will be collected in both groups.; Patients will receive standard of care. Patients need to fill in questionnaires, these are additional interventions for the included subject. Questionnaires for patient-reported outcomes (PROMs) and toxicity will be filled in one week before treatment, one week before re-irradiation, one week and three months after re-irradiation, one, two and five years after surgery.
Postoperative re-irradiation without hyperthermia; Postoperative re-irradiation without hyperthermia in patients with locoregional recurrent breast cancer	Other: No interventions, patient-reported outcomes (PROMs) and toxicity will be collected in both groups.; Patients will receive standard of care. Patients need to fill in questionnaires, these are additional interventions for the included subject. Questionnaires for patient-reported outcomes (PROMs) and toxicity will be filled in one week before treatment, one week before re-irradiation, one week and three months after re-irradiation, one, two and five years after surgery.
surgery only; Patients who do not receive postoperative re-irradiation after salvage mastectomy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-reported toxicity according to PRO-CTCAE in LRR patients	Patient-reported toxicity according to PRO-CTCAE after a median follow-up of five years after diagnosis of (subsequent) LRR disease.	Five years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life at 2 and 5 years after diagnosis of LRR disease	EORTC-C30	at 2 and 5 years after diagnosis of LRR disease
Quality of Life at 2 and 5 years after diagnosis of LRR disease	EORTC -BR45	at 2 and 5 years after diagnosis of LRR disease
LRR-free survival in LRR patients		at 2 and 5 years after diagnosis of LRR disease
distant metastasis-free survival in LRR patients		at 2 and 5 years after diagnosis of LRR disease
breast-cancer event-free survival in LRR patients		at 2 and 5 years after diagnosis of LRR disease
overall survival in LRR patients		at 2 and 5 years after diagnosis of LRR disease
Referral patterns in patients diagnosed with LRR	Referral patterns (per institute, professional, patient-related factors including performance status, and travel distance).	5 year

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Borstkanker Onderzoek Groep; Comprehensive Cancer Centre The Netherlands; Dutch Cancer Society
• Investigators: Principal Investigator: Desiree Van Den Bongard, Dr, Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: May 3, 2024
• First Submitted That Met QC Criteria: June 4, 2024
• First Posted (Actual): June 11, 2024

Study Record Updates

• Last Update Posted (Actual): July 16, 2026
• Last Update Submitted That Met QC Criteria: July 14, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: locoregional recurrence, breast cancer, treatment, re-irradiation, hyperthermia, patient-reported outcomes, quality of life, toxicity
• Additional Relevant MeSH Terms: Wounds and Injuries; Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Body Temperature Changes; Heat Stress Disorders; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Signs and Symptoms; Hyperthermia; Breast Neoplasms; Health Services Administration; Health Care Quality, Access, and Evaluation; Investigative Techniques; Epidemiologic Methods; Data Collection; Health Care Evaluation Mechanisms; Quality of Health Care; Public Health; Environment and Public Health; Health Care Economics and Organizations; Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Surveys and Questionnaires; Health Planning; Health Care Surveys; Health Services Research; Patient Outcome Assessment; Patient Reported Outcome Measures
• Other Study ID Numbers: 2012094

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No