Early initiation of external beam radiotherapy (EBRT) may increase the risk of long-term toxicity in patients undergoing intraoperative radiotherapy (IORT) as a boost for breast cancer

doi:10.1016/j.breast.2008.05.009

The Breast

Volume 17, Issue 6, December 2008, Pages 617-622

https://doi.org/10.1016/j.breast.2008.05.009 Get rights and content

Abstract

Background

Intraoperative radiotherapy (IORT) during breast-conserving surgery is increasingly used. We analyzed the influence of the interval between an IORT boost and external beam radiotherapy (EBRT) on late toxicity.

Methods

Forty-eight patients received 20 Gy IORT (50 kV X-rays (Intrabeam, Carl Zeiss, Oberkochen, Germany) followed by 46–50 Gy EBRT with a median interval of 36 days (14-197). Late toxicity was assessed with the modified LENT SOMA score after a median of 36 months.

Results

Twelve patients developed a higher grade fibrosis (°II–III), three teleangiectases, one a breast edema grade °II, six retractions, four hyperpigmentations and five pain (°II–III). The median interval between IORT and EBRT was significantly shorter in these patients (n = 18) compared to the 30 patients without higher grade toxicity (29.5 days vs. 39.5 days, p = 0.023, Mann–Whitney U-test).

Conclusion

Starting EBRT about 5–6 weeks after IORT appears to be associated with a decreased risk of chronic late toxicity compared with a shorter interval. The impact on local recurrence of prolonged gaps between IORT and EBRT is not known.

Introduction

Intraoperative radiotherapy (IORT) is currently being evaluated as a novel approach for partial breast irradiation. IORT can be used during breast-conserving surgery either as a tumor bed boost followed by external beam radiotherapy (EBRT1, 2, 3, 4, 5, 6, 7, 8) or as single treatment. Several studies investigating single dose IORT or accelerated partial breast irradiation (APBI) for early breast cancer are ongoing, e.g. TARGIT, ELIOT or NSABP B-39.9, 10

When IORT is given as a boost during breast-conserving surgery followed by EBRT and/or chemotherapy, timing and sequencing of the modalities may become crucial for the outcome of the patients as to local tumor control and toxicity. A long interval between IORT and EBRT may decrease local control rates because of tumor cell proliferation during the split. On the other hand, a too short interval may lead to increased chronic toxicity, e.g. tumor bed fibrosis when the overall treatment time is too short.

We evaluated the patients who were treated during the first two years after initiation of IORT for breast cancer in our institution for whom a 3-year follow-up is available. This is the first report analyzing the influence of the time interval between IORT and EBRT on the occurrence of late tumor bed fibrosis and other chronic toxicities.

Section snippets

Materials and methods

Between March 2002 and March 2004, 59 patients were treated with IORT during breast-conserving surgery followed by EBRT at the University Medical Center, Mannheim. Five patients died and six were lost to follow-up. The current analysis includes 48 patients with a median follow-up of 36 months after the end of EBRT (minimum 30 months, maximum 56 months, see Table 1).

IORT was given as previously reported.1, 2, 3, 4 In short, a dose of 20 Gy of 50 kV X-rays prescribed to the applicator surface was

Results

In general, late toxicity after IORT and EBRT was mild. Thirty out of 48 patients (63%) had no or only minor changes, i.e. toxicity °I at 3-year follow-up. Table 3 shows the complete list of side effects scored according to the LENT SOMA system. Chronic skin toxicity, especially telangiectasia and hyperpigmentation, was seen in less than 10% of the patients.

The rate of higher grade fibrosis was low with 11/48 patients having fibrosis °II–III of the tumor bed at 3-year follow-up. Any degree of

Discussion

IORT either as a boost followed by EBRT to the whole breast or as single modality APBI is increasingly used.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 However, little is known up to now about the long-term toxicity¹ and factors influencing cosmetic outcome. The interval between IORT and EBRT may be relevant for tumor cell kill and the development of normal tissue complications. Although we have previously reported the low local recurrence rate using this approach,⁶ this is the first report on toxicity after

Conclusion

In summary, although the number of toxicity events in this report is low, there was a clear, statistically significant and clinically relevant tendency for increased late toxicity when EBRT was initiated early after IORT. Eight out of 12 higher grade fibroses, 5 out of 6 retractions and 4 out of 5 breast pains were found when the IORT–EBRT interval was below the median of 36 days. Starting EBRT about 5–6 weeks after IORT appears to be associated with a decreased risk of chronic late toxicity

Conflict of interest statement

The authors state that they have no competing interests.

Authors’ contribution

F.W. was responsible for design and conception, involved in patient selection, responsible for final data analysis, responsible for writing and finalizing of the manuscript. G.W. and A.K. were responsible for data analysis and editing of the manuscript. E.B. and F.V. were involved in patient follow-up, clinical assessment and data analysis, and received informed consent for radiotherapy. C.H. was responsible for radiobiological modeling and interpretation of the data. O.T. and M.S. were

Acknowledgements

F.W. received funding for radiobiology research from Carl Zeiss Surgical, Oberkochen, Germany. The project is supported by grant FKZ 01ZP0508 from the BMBF and by the Dietmar-Hopp Foundation.

References (31)

U. Kraus-Tiefenbacher et al.
Long-term toxicity of an intraoperative radiotherapy (IORT) boost using low energy X-rays during breastconserving surgery (BCS)
Int J Radiat Oncol Biol Phys
(2006)
J.S. Vaidya et al.
Intraoperative radiotherapy for breast cancer
Lancet Oncol
(2004)
J. Vaidya et al.
Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost
Int J Radiat Oncol Biol Phys
(2006)
J. Vaidya et al.
Targeted intraoperative radiotherapy (Targit)—an innovative approach to partial breast irradiation
Semin Radiat Oncol
(2005)
M. Intra et al.
Surgical technique of intraoperative radiation therapy with electrons (ELIOT) in breast cancer: a lesson learned by over 1000 procedures
Surgery
(2006)
E. Van Limbergen et al.
Cosmetic evaluation of breast-conserving treatment for mammary cancer. 2. A quantitative analysis of the influence of radiation dose, fractionation schedules and surgical treatment techniques on cosmetic results
Radiother Oncol
(1989)
A. De la Rochefordiere et al.
Are cosmetic results following conservative surgery and radiation therapy for early breast cancer dependent on technique?
Int J Radiat Oncol Biol Phys
(1992)
D.A. Markiewicz et al.
The effect of sequence and type of chemotherapy and radiation therapy on cosmesis and complications after breast conservation therapy
Int J Radiat Oncol Biol Phys
(1996)
J.R. Gray et al.
Primary breast irradiation in large-breasted or heavy women: Analysis of cosmetic outcome
Int J Radiat Oncol Biol Phys
(1991)
C. Vrieling et al.
The influence of the boost in breast-conserving therapy on cosmetic outcome in the EORTC “boost versus no boost” trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer
Int J Radiat Oncol Biol Phys
(1999)

C. Vrieling et al.

Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC “boost versus no boost” trial

Int J Radiat Oncol Biol Phys

(1999)

C. Vrieling et al.

The influence of patient, tumor and treatment factors on the cosmetic results after breast-conserving therapy in the EORTC “boost vs. no boost” trial

Radiother Oncol

(2000)

U. Hoeller et al.

Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT SOMA scores

Int J Radiat Oncol Biol Phys

(2003)

U. Kraus-Tiefenbacher et al.

Intraoperative radiotherapy (IORT) as a boost in patients with early stage breast cancer—acute toxicity

Onkologie

(2006)

U. Kraus-Tiefenbacher et al.

Intraoperative radiotherapy (IORT) for breast cancer using the INTRABEAM system

Tumori

(2005)

Cited by (54)

Ten-year results of hypofractionated whole breast radiotherapy and intraoperative electron boost in premenopausal women
2022, Radiotherapy and Oncology
To evaluate outcome of intraoperative electron boost (IOERT) and hypofractionated whole breast irradiation (HWBI) for breast cancer (BC) in young women.
Women aged ≤ 48 with pT1-2 N0-1 BC received 12 Gy IOERT boost during conservative surgery followed by 3-dimensional conformal HWBI in 13 fractions (2.85 Gy/die). Local relapses (LR) and survival (disease-free, DFS; specific, BCSS; overall, OS) were analyzed.
481 consecutive BC patients, mostly node negative, with median age of 42 were treated between 2004 and 2014. Median tumor size was 1.48 cm and median IOERT collimator was 4 cm. After 25-day mean interval, HWBI was delivered. At a median follow-up of 9.6 years, there were 23 LRs (4.8 %, 9 of which were in the boost region). Ten-year LR cumulative incidence was 4.1 % (95 %CI, 2.5–6.3). Over time, local control rate decreased for Luminal A and HER2 positive with negative hormonal receptors, while remained steady for triple negative. At multivariate analysis, LR predictors included age < 40, extensive intraductal component and the use of 4-cm IOERT collimator size. Ten-year survival outcomes were as follows: DFS 80.0 % (95 % CI, 75.8–83.5), BCSS 97.5 % (95 % CI, 95.5–98.6 %), OS 96.5 % (95 % CI, 94.3–97.9). Luminal B HER2 negative had the worse survival outcomes. Perioperative complications were uncommon (16.4 %), acute toxicity was mild (<2% Grade 3), but moderate/severe fibrosis was described in 40.8 % of the cases. Cosmesis was scored as excellent/good in 86 % of the cases.
ELIOT boost and HWBI achieved an excellent local control at the cost of tumor bed fibrosis. IOERT boost dose lower than 12 Gy is advisable.
Breast-conserving surgery in breast cancer and intraoperative radiotherapy. Can we predict the fibrosis?
2019, Cirugia Espanola
Las técnicas de radioterapia asociadas a la cirugía conservadora del cáncer de mama precoz han evolucionado gracias a un mayor conocimiento de la radiobiología tumoral, destacando entre ellas la radioterapia intraoperatoria (RIO). Sin embargo, se han documentado complicaciones con dicha técnica, principalmente la fibrosis. El factor de crecimiento transformante beta (TGF-β) es una citocina relacionada con la fibrosis inducida después de la radiación que podría servir como marcador temprano del riesgo de desarrollo de la misma.
Estudio prospectivo multicéntrico de 60 pacientes a las que se les ha sometido a cirugía conservadora por cáncer de mama, asociada a RIO en 30 de ellas. Se evalúan los valores de TGF-β en muestras de suero preoperatorio y a las 24 h desde la cirugía, y de muestras de drenaje a las 6 y 24 h desde la cirugía.
Los valores de TGF-β objetivados en el suero y en el débito de drenaje a las 24 h desde la cirugía de las pacientes que recibieron RIO fueron significativamente mayores que los de aquellas que no la recibieron (p < 0,0001). De entre ellas, 8 pacientes presentaron valores superiores a 1.000 pg/ml. Estas diferencias entre los grupos no se modifican por el tipo de muestra utilizada, bien sea suero, bien débito de drenaje (p = 0,5881).
Aunque deben realizarse más estudios, valores elevados de TGF-β en las pacientes con cáncer de mama a las que se les realiza cirugía conservadora asociada a RIO pueden predecir el riesgo de fibrosis.
Radiotherapy techniques associated with breast-conserving surgery have evolved in early breast cancer thanks to a better knowledge of tumor radiobiology, highlighting intraoperative radiotherapy (IORT). However, complications have been documented with this procedure, mainly fibrosis. Transforming growth factor beta (TGF-β) is a cytokine with an active role in radiation-induced fibrosis, which could be used as an early biomarker for the development of fibrosis.
Multicentric prospective analysis of 60 patients with breast cancer who underwent breast-conserving surgery, 30 of whom had received additional IORT. TGF-β values were evaluated in serum pre-surgery and in serum collected 24 h after surgery. In addition, we evaluated surgical wound fluids collected 6 h and 24 h following surgery.
Serum and surgical wound fluids TGF-β values collected over 24 h following surgery were significantly higher in patients who received additional IORT (P < .0001). Notably, 8 of these patients showed values above 1,000 pg/ml. There were no differences between the samples (serum or surgical wound fluids) (P = .5881).
Although further investigation is needed, higher TGF-β values in IORT during breast-conserving surgery can be used as an early biomarker for the development of fibrosis.
Prevalence of pain in patients with breast cancer post-treatment: A systematic review
2018, Breast
To evaluate the prevalence and severity of persistent pain after breast cancer treatment (PPBCT) in patients who received surgery, radiotherapy or a combination of treatments and to explore how different treatments and techniques impact pain.
Medline, Embase and Cochrane Central databases were searched for articles which evaluated the prevalence of PPBCT. Search results were limited to studies addressing chronic post-surgical pain (CPSP), persistent post-surgical pain (PPSP), post-mastectomy pain syndrome (PMPS) or radiotherapy (RT) related pain in breast cancer patients and published in the English language. The primary outcome was the incidence or severity of PPBCT. Descriptive analyses were performed.
A total of 177 studies were included in this review. Overall, pain prevalence was 29.8% amongst 3746 patients (Group 1: 30 studies) post-surgery, 27.3% post-RT (Group 2: 41 studies, n = 15 019), and 21.8% amongst BC survivors who reported on the general prevalence of after receiving various combinations of BC treatment (Group 3: 106 studies, n = 135 437).
PPBCT remains to be a prevalent and complex clinical issue, despite a variety of different techniques and treatments. Various factors such as varying definitions of pain, inconsistent use of assessment tools and differences in methodology between studies may contribute to discrepancies in reports of PPBCT. A greater understanding of BC treatments and their impact on PPBCT may help identify potential risk factors, prevention and pain management strategies.
Risk factors for seroma evacuation in breast cancer patients treated with intraoperative radiotherapy
2016, Reports of Practical Oncology and Radiotherapy
Citation Excerpt :
It is estimated that 25% of all seromas require medical intervention immediately after IORT.29 The frequency of seroma is also affected by the reporting criteria.25 The present study is believed to be the first to investigate risk factors for seroma requiring evacuation >6 months after IORT.
Novel techniques in oncology provide new treatment opportunities but also introduce different patterns of side effects. Intraoperative radiotherapy (IORT) allows a shortened overall treatment time for early breast cancer either combined with whole breast radiotherapy (WBRT), or alone. Although the early side effects of IORT are well known, data on clinically important late side effects, which require medical intervention, are scarce.
In this study, we analyze risk factors for seroma evacuation more than 6 months after IORT.
We evaluated 120 patients with a mean follow-up of 27.8 months (range: 7–52 months). Fifty-one patients received IORT only and 69 were additionally treated with WBRT.
Seroma evacuation was performed 6–38 months after IORT. Two (3.9%) events were observed in the IORT group and 14 (20%) in the IORT + WBRT group. Univariate (Kaplan–Meier) analysis showed that addition of WBRT to IORT increased the risk of seroma evacuation [hazard ratio = 5.5, 95% confidence interval: 2.0–14.7, P = 0.011]. In a multivariate analysis (Cox proportional hazards regression), WBRT and axillary lymph node dissection were significant risk factors for seroma evacuation (model P value = 0.0025).
WBRT applied after IORT is associated with increased risk of seroma evacuation, which might be considered as a late side effect.
Major complications after intraoperative radiotherapy with low-energy x-rays in early breast cancer
2024, Strahlentherapie und Onkologie
A single-institution retrospective analysis of intraoperative radiation boost during breast-conservation treatment for breast cancer
2023, Journal of Cancer Research and Clinical Oncology

View all citing articles on Scopus

View full text

Original articleEarly initiation of external beam radiotherapy (EBRT) may increase the risk of long-term toxicity in patients undergoing intraoperative radiotherapy (IORT) as a boost for breast cancer

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusion

Conflict of interest statement

Authors’ contribution

Acknowledgements

Int J Radiat Oncol Biol Phys

Lancet Oncol

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

Surgery

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Intraoperative radiotherapy (IORT) as a boost in patients with early stage breast cancer—acute toxicity

Onkologie

Intraoperative radiotherapy (IORT) for breast cancer using the INTRABEAM system

Tumori

Original article
Early initiation of external beam radiotherapy (EBRT) may increase the risk of long-term toxicity in patients undergoing intraoperative radiotherapy (IORT) as a boost for breast cancer