|Year : 2018 | Volume
| Issue : 2 | Page : 84-88
Reirradiation in breast malignancies
Venkata Krishna Reddy Pilaka1, Kanhu C Patro1, Partha S Bhattacharyya1, Chitta R Kundu1, Madhuri Palla1, Rajesh Balakrishnan2
1 Department of Radiation Oncology, Mahatma Gandhi Cancer Hospital & Research Institute, Visakhapatnam, Andhra Pradesh, India
2 Department of Radiation Oncology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||31-Dec-2018|
Dr. Venkata Krishna Reddy Pilaka
Mahatma Gandhi Cancer Hospital & Research Institute, 1/7, MVP Colony, Visakhapatnam, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Ipsilateral breast or chest wall recurrence remains one the most common site of disease recurrence and significantly increases the morbidity and mortality. The current standard of care for ipsilateral breast tumour recurrence has been mastectomy. However, various recent studies showed that there is feasibility of repeat breast conservation surgery with reirradiation. Reirradiation in breast cancer is complicated approach. Many physicians are reluctant to reirradiate breast with restricted data available. This paper will review the current literature on reirradiation for locally recurrent breast cancer
Keywords: Reirradiation, breast cancer, local recurrence, whole breast radiation, post mastectomy radiation
|How to cite this article:|
Pilaka VK, Patro KC, Bhattacharyya PS, Kundu CR, Palla M, Balakrishnan R. Reirradiation in breast malignancies. J Curr Oncol 2018;1:84-8
| Introduction|| |
Data from several randomized trials have shown that locoregional recurrences occur in approximately 5%–15% of patients despite adjuvant radiotherapy after primary mastectomy or breast conservation surgery (BCS). Ipsilateral breast or chest wall remains the most common site of recurrence, comprising 60%–95% of all locoregional events.,,,, Early breast cancer trialists’ collaborative group meta-analysis reported that approximately one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10. The mortality reduction did not differ significantly between node positive and negative disease. Multiple retrospective studies have shown that local recurrence after curative treatment would lead to increased risk of distant metastases and breast cancer mortality.,, It is therefore essential to know the importance of treating the local recurrence in breast cancer so as to prevent distant metastases and breast cancer mortality. This article discusses various treatment options and techniques for local recurrences in breast cancer both after BCS and mastectomy.
The current standard of care for ipsilateral breast tumor recurrence (IBTR) is mastectomy. However, there is a large body of evidence, which describes repeat BCS in setting of locally recurrent disease. The local recurrence rates (LRRs) in repeat BCS alone are approximately 20%–40% at 5 years.,,,, In view of this, various trials have tested the feasibility of reirradiation to IBTR after BCS to minimize LRRs. Various methods of treatments such as external beam radiation therapy (EBRT), intraoperative radiation therapy (IORT), and brachytherapy have been described for reirradiation in breast cancer.
There are no definite guidelines for choosing second course of BCS for either new ipsilateral neoplasm or recurrent lesions. Local recurrences usually occur in the same quadrant, with similar histology and usually within 5 years of completion of treatment. Identifying second primary from recurrence is important as recurrence is independent predictor for breast cancer mortality, whereas prognosis of primary lesions depends on stage. Criteria for BCS have proposed for those with disease-free interval greater than 3 years, absence of late radiation changes in skin or breast tissue, early T stage (<3cm primary), and absence of involved nodes in new lesion. DEGRO of the German society of radiation oncology practical guidelines for radiotherapy in breast cancer, published in April 2016, defined selection criteria for second BCS after IBTR as: (a) isolated IBTR, (b) size <2–3cm, (c) unifocal disease on imaging, (d) age >50 years, (e) long interval between primary treatment and recurrence (>48 months), (f) patient’s preference, and also (g) technical feasibility of second BCS.
| Imaging Modalities to Detect Local Recurrence|| |
Various guidelines including the American Society of Clinical Oncology, European Society of Medical Oncology, and National Cancer Care Network guidelines recommend only history and physical examination every three monthly for 2 years and every six monthly thereafter and annual mammography.,,, Digital breast tomosynthesis delivers multiple thin images through the breast by acquiring mammographic projections at different angles. Even though it has been shown that there is increased detection rates and lesser false positive in screening programs, its role in detecting recurrences needs further research. Whole breast ultrasound has been used for evaluation of palpable breast abnormalities as well as evaluation of masses seen on mammography. No studies have been available for surveillance after BCS. Breast cancer subtype is also associated with development of local recurrences and distant metastases. Luminal B breast cancer has a higher hazard of breast cancer recurrence and shorter overall survival compared with Luminal A breast cancer. This differential pattern of recurrence might vary the schedule and intensity of surveillance accordingly in future.
| Second Breast-Conserving Surgery with Reirradiation|| |
With external beam radiation therapy
EBRT was used to reirradiate with IBTR as early as mid-1980s. Deutsch reported 40 women with IBTR following BCS and radiation therapy (RT). They received initial RT dose of 50 Gy to the whole breast in 2 Gy per fraction, with or without boost. Median time of recurrence was 63 months from initial treatment. Partial breast reirradiation (PBrI) to dose of 50 Gy in 2 Gy per fraction was delivered to entire operative quadrant using electrons of appropriate energy. Treatment was well tolerated but alternated in skin pigmentation. It was reported that 25% of evaluated patients were having fair to poor cosmesis. Würschmidt reported four patients receiving reirradiation with good cosmetic results and no grade 3 or higher toxicity.
RTOG 1014 results published 1-year toxicity report from a phase II study of repeat BCS and PBrI for IBTR in August 2017. Eligibility criteria included IBTR occurring more than 1 year after previous radiation, <3cm, unifocal, and resected with negative margins. PBrI was targeted to surgical cavity plus 1.5cm, prescription dose of 45 Gy in 1.5 Gy twice daily for 30 treatments. Sixty-five patients were accrued and treated. Treatment-related skin fibrosis and breast pain were recorded as grade 1 in 64% and grade 2 in 7% with only one patient with grade more than 3 and identified as grade 3 fibrosis of deep connective tissue. It was concluded that PBrI after second BCS is safe and feasible with acceptable treatment toxicity.
With intraoperative radiation therapy
In a single institution study, a total of 15 patients from Germany were treated by IORT with 50kV X-rays, applicator size of 4cm, which delivered single dose of 14.7–20 Gy to the applicator surface. No local recurrences were noted at median follow-up of 26 months (1–60 months). IORT was well tolerated with no grade 3 or higher toxicity with excellent cosmetic outcomes.
Brachytherapy after BCS for IBTR
The most solid evidence for reirradiation of IBTR exists for brachytherapy. The Groupe Européen de Curiethérapie and the European Society for Radiotherapy and Oncology (GEC-ESTRO) working group reported on a retrospective collaborative analysis of 217 patients with IBTR treated between 2000 and 2009 with multicatheter brachytherapy in eight European institutions. The median total doses delivered through low-dose rate (LDR) and pulsed-dose rate brachytherapy were 46 Gy (range, 30–55 Gy) and 50.4 Gy (range, 49–50 Gy), respectively. With high-dose rate (HDR) brachytherapy, the median dose delivered was 32 Gy (range, 22–36 Gy; equivalent dose in 2-Gy fractions: 43 Gy4) in 5–10 fractions (median, 8 fractions) (twice daily). With a median follow-up of 3.9 years (1.1–10.3 years) after IBTR retreatment, the 5- and 10-year actuarial second LRRs were 5.6% (1.5%–9.5%) and 7.2% (2.1%–12.1%), respectively. The grade 3 and 4 complication rates were 10% and 1% (ulceration), respectively. Excellent or good cosmetic results were achieved in 85%. In comparison to salvage mastectomy series, results were reported to be at least equivalent with 5- and 10-year actuarial rates for metastatic recurrence of 9.6% and 19.1%, disease-free survival of 84.6% and 77.2%, and overall survival of 88.7% and 76.4%, respectively. Further single-institution studies with few patients support these data.,,,
A French retrospective study of almost 70 patients who underwent repeat lumpectomy followed by interstitial brachytherapy revealed promising 5-year Overall survival (OS) and freedom from second local recurrence (FFLR2). A 77% rate of FFLR2 was noted in 70 patients. Interestingly, in this group of patients treated with interstitial brachytherapy, multivariate analysis revealed the subset of patients treated with five or more wires had a markedly improved FFLR2 of nearly 95% at 5 years. This treatment was well tolerated with minimal acute toxicity, and only 10% rate of late grade 3 toxicity was noted, most commonly fibrosis.
A much larger retrospective series of 217 patients receiving second conservative treatment with lumpectomy and interstitial brachytherapy was reported on at the World Congress of Brachytherapy in 2012. The 5-year LRR was a promising 5.6% with actuarial OS at 5 years reported as 88.7%. Furthermore, cosmesis was good to excellent in 85% of patients with an 11% rate of grade 3 and 4 toxicity noted.
A smaller phase I/II study used LDR brachytherapy, initially to a total dose of 30 Gy in six patients. The dose was escalated to 45 Gy for the subsequent nine patients as toxicity was minimal. Consistent with the majority of data, an admixture of systemic therapy was reported with a portion of patients receiving chemotherapy or hormonal therapy.
In this phase I/II trial, Chadha et al. reported an 89% local control rate, but the number of patients was low and median follow-up was only 36 months. However, similar 5-year actuarial local control of 93% was seen in the larger Austrian study with a median follow-up of 57 months. In this study, 5-year OS and disease free survival (DFS) were 87% and 77%, respectively. Ten-year actuarial data were reported in the Spanish study, showing an OS of 96.7%, DFS of 64.4%, and local control of 89.4%.
Guix et al. analyzed long-term results of pilot study conducted on 36 patients with breast-only recurrences less than 3cm in diameter, who underwent HDR brachytherapy (30 Gy in 12 fractions over 5 days) and reported low treatment-related toxicity, with no grade 3 or 4 events reported. Cosmetic results were satisfactory in 90.4%. Kauer-Dorner et al. noted grade 3 breast tissue fibrosis in one woman and three women had grade 3 pain. Poor or unacceptable cosmesis was documented in six patients by independent observers; however, only two patients self-reported this level of cosmetic outcome. Thus, equivalent local tumor control to mastectomy was obtained by second breast conservation therapy with good cosmesis and moderate morbidity. Overall, the addition of PBrI to repeat breast-conserving surgery appears to be both efficacious and well tolerated. However, when considering the use of a second breast-conserving therapy, it is important to remember that the study populations were highly selected patients with small local recurrences occurring more than 1 year from initial treatment.
| Repeat Chest Wall Irradiation for Local Recurrence after Mastectomy|| |
Repeat chest wall radiotherapy is controversial because of high cumulative doses that would cause potential toxicity. Local control with repeat surgery alone remains unacceptable with 5-year local control rates of only 33%. Therefore, the use of repeat chest wall RT has been explored for a second curative intent treatment despite the concerns over possible toxicity.
In a multi-institutional study conducted by Wahl et al., 81 patients underwent reirradiation of the breast or chest all for local recurrence. The median dose of the first course of radiation was 60 Gy and was 48 Gy for second course. Median dose for the second treatment course was 48 Gy. Two-thirds of patients were free of local disease at 12 months, with the local DFS rate significantly higher in patients without gross disease. Overall, the complete response rate was 57%. Three grade 3 late toxicities occurred with patients experiencing fibrosis, infection, and lymphedema. The lone grade 4 event, dermatitis, occurred in a patient who had a cumulative RT dose of ≥120 Gy.
Müller et al. reviewed the data on the role of repeat surgery and chest wall reirradiation for curative intent. Forty-two women had received an initial median dose of 54 Gy and after local recurrences received either surgery followed by chest wall reirradiation or chest wall reirradiation alone. The second course of RT was conventionally fractionated to a median dose of 60 Gy. The median interval between courses of RT was slightly longer than that reported by Wahl et al., 53 versus 38 months. At a median follow-up of 41 months, the estimated 5-year local control was 62% and 5-year OS was 59%. Only two cases of acute grade 3 skin toxicity were noted. Eight cases of late grade 3 skin toxicity were reported and no acute or late grade 4 toxicity occurred.
Laramore et al. reported a study on 13 patients treated with conventionally fractionated electrons for chest wall recurrences. All patients had received previous postoperative chest wall irradiation with doses between 40 and 50 Gy. Of these patients, 62% were alive and free of local disease after a median follow-up of 12 months. Skin reactions were limited to temporary erythema and dry or moist desquamation.
These studies indicate that chest wall reirradiation can provide an improved prognosis for women with local recurrence and can be administered with acceptable acute and late toxicities following initial treatment of breast cancer with surgery and postoperative RT. Simultaneous radiochemotherapy as a treatment option has been investigated in a limited number of trials.
| Reirradiation with or without Hyperthermia|| |
Jones et al. enrolled 109 patients with superficial tumors (70 patients with breast cancer) in a prospective randomized trial comparing irradiation of chest wall recurrences with irradiation and additional hyperthermia. The complete response rate was 66.1% in the hyperthermia and 42.3% in the irradiation-only arm. Previously irradiated patients had the greatest incremental gain in complete response: 23.5% in the non-hyperthermia versus 68.2% in the hyperthermia arm. No OS benefit was seen. The authors concluded that adjuvant hyperthermia resulted in a significant local control benefit in patients with superficial tumors receiving RT. The data were supported by a meta-analysis of five randomized trials including 306 patients with advanced primary or recurrent breast cancer. The complete remission rate was significantly improved in patients treated with combined radiation and hyperthermia compared to radiation alone (59% vs. 41%). OS was not improved.
More recent data were published in a retrospective analysis of 198 patients who underwent either R0 (n = 107) or R1 resection (n = 91) for recurrent breast cancer. Hyperthermia was used as an adjunct to reirradiation (eight 4-Gy fractions). After a median follow-up of 42 months, the 5-year locoregional control rate was 78%. The 5-year grade 3/4 late toxicity rate amounted to 11.9% (n = 15 skin ulcerations, n = 5 osteoradionecrosis of the ribs). The same working group investigated 248 patients with a macroscopic breast cancer recurrence treated with reirradiation and hyperthermia. After a median follow-up of 32 months, 70% of patients had a complete remission. The 5-year local control rate was 39%. Thermal burn was developed by 23% of patients, which healed with conservative measures. The incidence of 5-year late grade 3 toxicity was 1%.
| Contouring Guidelines for Partial Breast Reirradiation After Repeat BCS for IBTR (Adopted from RTOG 1014)|| |
The excision cavity should be outlined based either on clear visualization on CT or, if placed, with the help of surgical clips. The clinical target volume (CTV) should be defined by uniformly expanding the excision cavity volume by 15mm. The CTV should be limited to 5mm from the skin surface and by the posterior breast tissue extent (chest wall structures and pectoralis muscles are not to be included). The planning target volume (PTV) should provide a margin around the CTV to compensate for the variability of treatment setup and motion of the breast with breathing. The PTV should be defined as a minimum of 10mm around the CTV (superior, inferior, medial, and lateral dimension) to account for anticipated breathing motion and setup uncertainty.
The PTV is saved and is used to generate the beam aperture (with an additional margin to take penumbra into account). PTV for Evaluation (PTV_EVAL) is generated for dose volume histogram (DVH) constraints and analysis as substantial part of the PTV often extends outside the limits of breast tissue an additional contour. PTV_EVAL is limited to exclude the part outside the ipsilateral breast and the first 5mm of tissue under the skin (to remove most of the buildup region for the DVH analysis) and to exclude the PTV expansion beyond the posterior extent of breast tissue (chest wall, pectoralis muscles, and lung). This PTV_EVAL should not be used for beam aperture generation.
| Roleof Systemic Therapyin Isolated Local Breast Cancer Recurrence|| |
Various National Surgical Adjuvant Breast and Bowel Project protocols showed a higher risk of distant metastases and an increase in mortality rates following ipsilateral locoregional recurrence. But in view of inadequate evidence, the role of chemotherapy is still controversial. The CALOR (Chemotherapy as Adjuvant for Locally Recurrent breast cancer) study is a randomized trial that randomized patients into no chemotherapy or investigator’s choice of four cycles of chemotherapy. Patients with estrogen receptor (ER) positive disease received adjuvant therapy, and anti-human epidermal growth factor receptor 2 (HER2) therapy was optional. At a median follow-up of 4.9 years, the disease-free survival was better in chemotherapy arm. However, patients with ER-negative disease benefited most with adjuvant chemotherapy. But with slow accrual and less number of patients recruited than the intended sample size (162 of 1000 patients), it is difficult to interpret the conclusions. Adjuvant hormonal therapy is recommended in all patients with hormone-positive tumors, irrespective of administration of chemotherapy. Patients who are premenopausal are treated with tamoxifen and switched over to aromatase inhibitors if they are postmenopausal or had ovarian ablation. Trastuzumab or lapatinib can be used in HER2-positive disease.
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