Toxicity and Outcome of Whole Breast Hypofractionated Radiotherapy: a Single Institution Experience (Ipomammella)

April 19, 2025 updated by: Andrei Fodor, MD, IRCCS San Raffaele

Toxicity and Outcome of Whole Breast Hypofractionated Radiotherapy Without Boost: Results of a Homogeneous Single Institution Experience

This is a homogeneous, single institution, observational, non-interventional, prospective study of 500 patients who will be treated according to the standard protocol of adjuvant hypofractionated radiotherapy after breast conserving surgery, at a total dose of 40 Gy/ 15 fr (5 fr/ week, 3 consecutive weeks). In addition to the regular follow up, the patients will respond to the quality-of-life questionnaires (QLQ) of the European Organisation for Research and Treatment of Cancer (EORTC), general, QLQ- C30, and specific for breast (BR), QLQ- BR23, at the first visit, at the end of radiotherapy and at the subsequent follow-up visits from 6 months up to 5 and a half years, to evaluate the quality of life during and after the treatment.

The study also has a retrospective arm of approximately 3300 patients (number of patients and characteristics of disease expanded with the amendment presented to the Lombardia 1 Ethics Committee in May 22/2024), treated from January 2009, for whom disease control and toxicity will be evaluated.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The study is observational, homogeneous (performed in a single institution), non-interventional, and composed of two parts: one retrospective and one prospective (for which we request the registration in the register of clinical trials).

The patients with breast cancer treated with adjuvant hypofractionated radiotherapy at the Department of Radiotherapy of "San Raffaele Scientific Institute" (IRCCSSRaffaele) from January 2009 will be identified and their clinical and dosimetric data retrieved and analyzed.

The objectives of the retrospective arm of the study are the analysis, with a follow up of 5 years, of acute and late toxicity, and clinical outcomes, such as local and regional control, overall survival, disease free survival and cancer-specific survival. A secondary objective is the identification of prognostic factors for toxicity and disease progression.

With the amendment approved by the Ethics Committee 1 of Lombardy Region in 22/05/2024 (CET Em. 195-2024) the number of patients in the retrospective arm was expanded to 3300. Were included: patients treated with moderate hypofractionated or ultra-hypofractionated radiotherapy to whole breast+/- simultaneous integrated boost to surgical bed, patients treated with accelerated partial breast irradiation, patients treated with hypofractionated radiotherapy to regional nodal irradiation and whole breast+/-SIB to surgical bed. The follow-up period was expanded to 10 years.

The objective of the prospective arm of the study, for a cohort of 500 consecutive patients who agree to participate in the study, is to assess the quality of life of the patients treated with hypofractionated short course (3 weeks) radiotherapy. The quality-of-life questionnaires (QLQ) of the European organization for research and treatment of cancer (EORTC): QLQ-C30 (general) and QLQ-BR23 (specific for the breast), will be distributed before radiation treatment, at the time of patient enrollment, at the end of therapy and during the follow up visits, for a duration of 5 years after the first follow up, scheduled first at 6 months and then annually.

Given the non-interventional, observational nature of the study, the follow up program of the patients with breast cancer, treated according to the standard departmental protocol, will not be modified. The patients will be identified from the patient data base from medical records retrieved from the radiotherapy archive, and the images monitoring local evolution from the photo archive. The data will be extracted from medical records. In addition, the dosimetric data of the treatments will be recovered from the physical dosimetric archives and the extrapolated data will be correlated with clinical and toxicity outcomes.

For the patients of the prospective observational arm, the dosimetric data and quality of life questionnaires, as well as the follow up visit results, will be prospectively collected, registered in a data base, and subsequently analyzed.

The toxicity registered during the visits carried out during the treatment will be determined using the Radiation Therapy Oncology Group (RTOG) scale; the Scoring system of late effects of radiation on normal tissues (SOMA-LENT scale) will be used for toxicity registered during the follow up visits. The clinical points analyzed will include: quality of life, overall survival, disease free- and cancer specific-survival, local and regional control, distant metastasis free survival, acute and late toxicity, physical dosimetry and aesthetic results. The correlation between detected parameters will be evaluated for the identification of prognostic factors. Statistical analyses will be performed with SPSS software version 17.0 (SPSS Inc. Released 2008; SPSS Statistic for Windows, Version 17.0. Chicago, USA: SPSS Inc.) and MedCalc v.12.1.4.0 (MedCalc Software, Ostend, Belgium) and any updated version. Statistical tests to be used will include: uni- and multi-variate logistic regression to define predictors of incidence and prevalence of toxicity and local/ distant relapses; Cox model ( proportionally-hazard regression) uni- and multi-variate for actuarial analysis of predictors of toxicity and local/ distant relapses; Wilcoxon matched -pair test for the quality of life index variations; Spearman test for the correlation between continuous variables, ANOVA test for the effect of treatment variables on changes in QoL scores over time.

*Enrollment in the quality-of-life study was suspended in November 2021 due to patients' refusal to participate during the Sars-Cov2 pandemic, the adoption of shorter schedule protocols to minimize patient hospital visits, the adoption of a simultaneous integrated boost for patients with high risk of local relapse(TNBC, HER2+) requiring a change in the technique utilized.

Study Type

Observational

Enrollment (Actual)

410

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • MI
      • Milan, MI, Italy, 20132
        • IRCCS San Raffaele Scientific Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Breast cancer patients treated with surgery (conservative/mastectomy), and hypofractionated/ultrahypofractionated radiotherapy to surgical bed or whole breast +/-SIB, +/- regional lymph nodes

Description

Inclusion Criteria:

  • Breast cancer patients with TNM Classification of Malignant Tumours pathological stage Tis-T4d, N0-N3, treated with surgery (conservative or mastectomy), accelerated partial breast irradiation or whole breast hypofractionated radiotherapy +/-SIB +/- regional lymph node irradiation

Exclusion Criteria:

- male breast cancer patients

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Quality of life
Quality of life of breast cancer patients treated with conservative surgery (quadrantectomy) and adjuvant hypofractionated whole breast radiotherapy according to the institutional standard regimen, to a total dose of 40 Gy in 15 fraction over 3 weeks will be measured with EORTC quality of life questionnaires QLQ-C30 and QLQ-BR23, before the start of the radiotherapy, at the end of the radiotherapy and subsequently at every follow-up visit (the first at 6 months after the end of the treatment, then annually for 5 consecutive years after the first follow up visit).
Other: Quality of life measurement
The quality of life of breast cancer patients treated with conservative surgery and adjuvant whole breast hypofractionated radiotherapy, without boost, will be evaluated.
Breast cancer, retrospective

In the observational retrospective cohort patients with histologically confirmed breast cancer treated with hypofractionated/ultrahypofractionated radiotherapy to:

  • whole breast +/- Simultaneous Integrated Boost (SIB) to surgical bed,
  • breast/chest wall and lymph node areas +/- SIB to surgical bed,
  • surgical bed only, with accelerated partial breast irradiation,

using 3D conformal radiotherapy or advanced radiotherapy techniques (IGRT, IMRT, SBRT) will be included.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
quality of life after hypofractionated adjuvant radiotherapy
Time Frame: up to 66 months
degree of general quality of life worsening of patients treated with hypofractionated adjuvant radiotherapy after breast conserving surgery assessed with EORTC quality of life questionnaires QLQ C30
up to 66 months
breast specific quality of life after hypofractionated adjuvant radiotherapy
Time Frame: up to 66 months
degree of specific quality of life worsening of patients treated with hypofractionated adjuvant radiotherapy after breast conserving surgery assessed with EORTC quality of life questionnaire QLQ BR23
up to 66 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Local Relapse Free Survival
Time Frame: From the date of radiotherapy end until the date of local progression or date of death from any cause, whichever came first, assessed up to 120 months
Local control of the disease (at the treated site)
From the date of radiotherapy end until the date of local progression or date of death from any cause, whichever came first, assessed up to 120 months
Disease Free Survival
Time Frame: From the date of radiotherapy end until the date of first documented clinical progression or date of death from any cause, whichever came first, assessed up to 120 months
Absence of disease progression during the follow-up
From the date of radiotherapy end until the date of first documented clinical progression or date of death from any cause, whichever came first, assessed up to 120 months
Regional Relapse Free Survival
Time Frame: From the date of radiotherapy end until the date of regional progression or date of death from any cause, whichever came first, assessed up to 120 months
Regional control (at the regional lymph node chains)
From the date of radiotherapy end until the date of regional progression or date of death from any cause, whichever came first, assessed up to 120 months
Distant Metastases Free Survival
Time Frame: From the date of radiotherapy end until the date of distant progression or date of death from any cause, whichever came first, assessed up to 120 months
Distant metastasis developed after the treatment
From the date of radiotherapy end until the date of distant progression or date of death from any cause, whichever came first, assessed up to 120 months
Cancer Specific Survival
Time Frame: From the date of radiotherapy end until the date of death from disease progression, assessed up to 120 months
Cancer survival
From the date of radiotherapy end until the date of death from disease progression, assessed up to 120 months
Overall survival
Time Frame: From the date of radiotherapy end until the date death from any cause, assessed up to 120 months
Survival from all causes
From the date of radiotherapy end until the date death from any cause, assessed up to 120 months
Acute toxicity
Time Frame: Up to three months from the start of radiotherapy
Acute toxicity after hypofractionated whole breast adjuvant radiotherapy evaluated with CTCAE (Common Terminology Criteria for Adverse Events) scale v 5.0, which displayes grades from 1 to 5, with grade 1 mening mild toxicity and grade 5 death related to toxicity
Up to three months from the start of radiotherapy
Late toxicity
Time Frame: From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 120 months
Toxicity developed after three months until the end of follow-up or death, assessed with Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale, which displayes grades from 1 to 5, with grade 1 meaning mild toxicity and grade 5 death related to toxicity
From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 120 months
Late skin toxicity
Time Frame: From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 120 months
Toxicity developed after three months until the end of follow-up or death, assessed with LENT-SOMA scale, which displayes grades from 1 to 4, with grade 1 meaning mild toxicity and grade 4 worst toxicity
From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 120 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Aesthetic result
Time Frame: From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 120 months
Assessment of the effect of radiation therapy with photographs taken the day of treatment planning verification (before the first radiotherapy fraction), after 15 fractions of radiotherapy (at the end of radiation therapy), and during follow-up visits (the first 6 months after the end of radiotherapy and than at 18 months, 30 months, 42 months, 54 months and 66 months after the end of radiotherapy).
From three months after the start of radiotherapy until the end of follow-up or death, assessed up to 120 months
Predictive factor for disease progression and death
Time Frame: From radiotherapy end to date of local, regional progression, distant failure, or death, assessed up to 120 months
actors predicting survival. Survival trees, univariate/multivariate Cox regression models will be estimated to identify potential risk factors associated with survival outcomes
From radiotherapy end to date of local, regional progression, distant failure, or death, assessed up to 120 months
Radiomic predictive factors for disease progression and death
Time Frame: From radiotherapy end to the first registered event (disease progression or death), assessed up to 120 months
Simulation CT radiomic features predicting relapse or death will be extracted, acording to IBSI (Image Biomarker Standardisation Initiative), owning to the different families of features: Morphology, Statistical, Intensity Histogram, Grey Level Cooccurrence Matrix 3D-average, Grey Level Co-occurrence Matrix 3D-combined, Grey Level Run Lenght 3D-average. Grey Level Run Lenght 3D_combined, Grey Level Size Zone Matrix 3D, Neighbors Grey Tone Difference Matrix 3D, Grey Level Distance Zone Matrix 3D, standard convolutional filters within radiomic workflow (wavelets, Laplacian of Gaussian
From radiotherapy end to the first registered event (disease progression or death), assessed up to 120 months
Predictive factors for toxicity
Time Frame: From radiotherapy start until the end of follow-up or death, assessed up to 120 months
Factors predicting toxicity. Survival trees, univariate/multivariate Cox regression models will be estimated to identify potential risk factors associated with toxicity
From radiotherapy start until the end of follow-up or death, assessed up to 120 months
Radiomic predictive factors for toxicity
Time Frame: From radiotherapy start until the end of follow-up or death, assessed up to 120 months
Simulation CT radiomic features predicting toxicity will be extracted, acording to IBSI (Image Biomarker Standardisation Initiative), owning to the different families of features: Morphology, Statistical, Intensity Histogram, Grey Level Cooccurrence Matrix 3D-average, Grey Level Co-occurrence Matrix 3D-combined, Grey Level Run Lenght 3D-average. Grey Level Run Lenght 3D_combined, Grey Level Size Zone Matrix 3D, Neighbors Grey Tone Difference Matrix 3D, Grey Level Distance Zone Matrix 3D, standard convolutional filters within radiomic workflow (wavelets, Laplacian of Gaussian)
From radiotherapy start until the end of follow-up or death, assessed up to 120 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS San Raffaele

Investigators

  • Principal Investigator: Andrei Fodor, M.D., IRCCS San Raffaele Scientific Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2016

Primary Completion (Estimated)

November 30, 2026

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

February 16, 2017

First Submitted That Met QC Criteria

March 6, 2017

First Posted (Actual)

March 10, 2017

Study Record Updates

Last Update Posted (Actual)

April 22, 2025

Last Update Submitted That Met QC Criteria

April 19, 2025

Last Verified

April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Ipomammella

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The data that support the findings of this study (anonymized individual participant data) are available on request from the corresponding author to researchers who provide a methodologically sound proposal. Requests made to the corresponding author (AF) will be evaluated by the Lombardy Territorial Ethics Committee 1.

IPD Sharing Time Frame

for 2 years after the study closes

IPD Sharing Access Criteria

Request from the corresponding author approved by the Lombardy Territorial Ethics Committee 1

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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