Radiation-Associated Angiosarcoma of the Breast and Chest Wall Treated with Thermography-Controlled, Contactless wIRA-Hyperthermia and Hypofractionated Re-Irradiation

Simple Summary This retrospective study reports on 10 patients with radiation-associated angiosarcoma of the breast and chest wall treated during the past decade. In this rare disease local control is highly dependent on the extent of surgery. Further treatment options are urgently needed. Re-iradiation in combination with localized hyperthermia should be considered for adjuvant and definitive treatment of nonresectable radiation-associated angiosarcomas. The presented hypofractionated re-irradiation schedule with 5 × 4 Gy once per week immediately following wIRA-hyperthermia is a promising option to further reduce the radiation dose recommended so far. This could reduce side effects without compromising local control. Abstract Background: Radiation-associated angiosarcoma of the breast (RAASB) is a rare, challenging disease, with surgery being the accepted basic therapeutic approach. In contrast, the role of adjuvant and systemic therapies is a subject of some controversy. Local recurrence rates reported in the literature are mostly heterogeneous and are highly dependent on the extent of surgery. In cases of locally recurrent or unresectable RAASB, prognosis is very poor. Methods: We retrospectively report on 10 consecutive RAASB patients, most of them presenting with locally recurrent or unresectable RAASB, which were treated with thermography-controlled water-filtered infrared-A (wIRA) superficial hyperthermia (HT) immediately followed by re-irradiation (re-RT). Patients with RAASB were graded based on their tumor extent before onset of radiotherapy (RT). Results: We recorded a local control (LC) rate dependent on tumor extent ranging from a high LC rate of 100% (two of two patients) in the adjuvant setting with an R0 or R2 resection to a limited LC rate of 33% (one of three patients) in patients with inoperable, macroscopic tumor lesions. Conclusion: Combined HT and re-RT should be considered as an option (a) for adjuvant treatment of RAASB, especially in cases with positive resection margins and after surgery of local recurrence (LR), and (b) for definitive treatment of unresectable RAASB.


Introduction
Radiation-associated (secondary) angiosarcoma of the breast (RAASB) is a highly aggressive tumor that develops in previously irradiated areas. It occurs due to the utilization of adjuvant radiotherapy (RT) mostly applied in the setting of breast-conserving treatment in breast cancer. c-Myc amplification in RAASB is characteristic and differentiates RAASB  Median latency period of RAASB was 6 years (range: 4.5-14) ( Table 2). Clinical observations such as skin type, hair color, the presence of benign and RT-related skin alterations were also recorded. Five out of 10 patients presented with ruby points (cherry hemangiomas), and 2 patients with fibrosis (thickening of the skin) ( Table 2).

RT-Technique
Tumor extensions at time of presentation at the RT department were divided into 4 categories: I = postoperative after R0, II = postoperative after incomplete resection (inappropriate resection margin, R1, or R2 respectively), III = macroscopic lesions, limited to the ipsilateral chest wall, not surpassing midsternal line, midaxillary line, clavicle or lower costal margin, and IV = macroscopic lesion with far-reaching extension, reaching the contralateral chest wall, supraclavicular fossa, abdominal wall or the back. In addition, depth of infiltration as a putative prognostic factor was classified as follows: a = infiltration limited to cutis and subcutis, and b = deep infiltration into the muscle layer ( Figure 1). None of the patients presented with distant metastases from RAASB.  <10  <10  <10  <10  <10  >10  >10  >10   ing  3  3  2  3  3  2  3  3  3  3  Type  II  I  II  II  II  II  I  I  I  I  ir  brown  red  brown  fair  brown  brown  fair  fair  fair  Tumor extensions at time of presentation at the RT department were divided into 4 categories: I = postoperative after R0, II = postoperative after incomplete resection (inappropriate resection margin, R1, or R2 respectively), III = macroscopic lesions, limited to the ipsilateral chest wall, not surpassing midsternal line, midaxillary line, clavicle or lower costal margin, and IV = macroscopic lesion with far-reaching extension, reaching the contralateral chest wall, supraclavicular fossa, abdominal wall or the back. In addition, depth of infiltration as a putative prognostic factor was classified as follows: a = infiltration limited to cutis and subcutis, and b = deep infiltration into the muscle layer ( Figure 1). None of the patients presented with distant metastases from RAASB. Figure 1. Different RAASB categories as used in this retrospective study. I = postoperative after R0, II = postoperative after incomplete resection (inappropriate margin, R1, or R2 respectively), III = macroscopic lesion limited to ipsilateral chest wall, not surpassing midsternal and midaxillary line, clavicle and lower costal margin, IV = macroscopic lesion with far-reaching extension, more than ipsilateral chest wall and supraclavicular fossa and/or contralateral chest wall or breast and/or abdominal wall and/or extension on the back. Lower right panel: Additional information on infiltration depth: a = infiltration limited to skin/subcutis, b = deep infiltration into muscle layers.

Patient Groups
According to their different histories, patients were divided into 4 groups A-D (Table 3):  with preoperative biopsy mapping. In both patients the option of another extensive surgery was abandoned due to the almost immediate recurrence with rapid extension over the chest wall.
Group D: 3 patients (No. 8, 9, and 10) presented with large-sized unresectable recurrences of RAASB, patients No. 8 and 9 in a highly palliative situation. Patient No. 8 had been heavily pretreated (e.g., 2 resections, 7 chemotherapies) and presented after the 3rd RAASB recurrence with a tumor infiltrating into the muscle layer, and No. 9 presented with a large tumor extending to the back. Patient No. 10 presented in a good general condition.

Treatment
Treatment planning was based on CT scan, former radiological investigations, e.g., MRI and PET-CT and clinical descriptions to define properly lateral tumor spread and deep infiltration. RT-and HT-volumes were prescribed with margins of 5 to 10 cm around all visible lesions whenever possible. That means that RT-fields, mostly using electrons, were quite large and mainly limited by the machines' capability. Electrons were chosen because RAASB is considered a skin disease occurring in cutaneous/subcutaneous layers. The treatment protocol consisted of weekly water filtered infrared-A (wIRA) superficial HT for 45-60 min (hydrosun ® TWH1500, Hydrosun Medizintechnik, Müllheim, Germany, see Figure 2D), immediately followed by re-RT. The contactless energy deposition allows for continuous thermography as well as visual control of the entire treatment field, which is of crucial importance for critical skin conditions, e.g., skin transplants and mesh grafts ( Figure 2C,F). In addition, this technique produces very large treatment fields [30], mostly even larger than radiation fields in order to cover completely the defined treatment volume. The computer-based, closed feedback system of this device was set at a maximum skin surface temperature of 43.0 • C ( Figure 2E). This results in tissue temperatures >40 • C at a tissue depth up to approximately 15 mm, and >39 • C up to a depth of 25-30 mm [30]. Patients No. 1-9 were treated with 4 Gy once per week for a total dose of 20 Gy, as described in detail later [28][29][30]. Eight patients were irradiated with 6-9 MeV electrons and a preheated bolus. Patient No. 8 had a combined photon-electron plan to cover deep infiltration. Patient No. 10 received a conventionally fractionated re-RT with 50 Gy (25 fractions with 2 Gy/fraction with photons) with an electron boost up to 60 Gy which was combined with 6 weekly hyperthermia sessions, applied immediately before RT.

Treatment Outcome
Both patients of Group A (adjuvant HT/re-RT after primary surgery of RAASB) did not develop a recurrence during follow-up (FU), with patient No. 1 (Figure 3 A-D) being observed for 67 months before being lost to FU (LFU), and patient No. 2 for 37 months still currently under observation today.

Treatment Outcome
Both patients of Group A (adjuvant HT/re-RT after primary surgery of RAASB) did not develop a recurrence during follow-up (FU), with patient No. 1 (Figure 3 A-D) being observed for 67 months before being lost to FU (LFU), and patient No. 2 for 37 months still currently under observation today. In Group B (adjuvant HT/re-RT after surgery of recurrent RAASB), patient No. 3 with R1 resection developed a re-recurrence at the border after 6 months which was directly retreated with the same HT/re-RT schedule, resulting in complete remission (CR) ( Figure  3A-F). Afterwards, the patient received palliative chemotherapy with paclitaxel due to distant metastasis and developed a new local progression in-and outside the former treatment fields. The patient died 20 months later. Patient No. 4, who initially had an R1 In Group B (adjuvant HT/re-RT after surgery of recurrent RAASB), patient No. 3 with R1 resection developed a re-recurrence at the border after 6 months which was directly retreated with the same HT/re-RT schedule, resulting in complete remission (CR) ( Figure 3A-F). Afterwards, the patient received palliative chemotherapy with paclitaxel due to distant metastasis and developed a new local progression in-and outside the former treatment fields. The patient died 20 months later. Patient No. 4, who initially had an R1 resection, developed three consecutive re-recurrences, the first after 3 months. All re-recurrences were retreated with the same HT/re-RT schedule (5 × 4 Gy, which was repeated three times in total), each time resulting in CR. This patient is currently (45 months after surgery of the first recurrence of RAASB) under observation with slow progression. Documentation is shown in Figure 4A-L. Patient No. 5 with R0 resection is still alive after 10 months, and currently has no evidence of disease (NED).
Cancers 2021, 13, 3911 9 of 17 resection, developed three consecutive re-recurrences, the first after 3 months. All re-recurrences were retreated with the same HT/re-RT schedule (5 × 4 Gy, which was repeated three times in total), each time resulting in CR. This patient is currently (45 months after surgery of the first recurrence of RAASB) under observation with slow progression. Documentation is shown in Figure 4A-L. Patient No. 5 with R0 resection is still alive after 10 months, and currently has no evidence of disease (NED).   In Group C (macroscopic recurrence 3-4 weeks after primary radical surgery) patient No. 6 achieved a CR and has been locally controlled for 16 months, with NED. Patient No. 7 has just finished the treatment.
In Group D (unresectable RAASB recurrences) patient No. 8 did not respond to HT/re-RT and died after 1 month. Patient No. 9 achieved a PR with good palliative effect and survived for 7 months. The clinical situation is presented in Figure 5A,B. Patient No. 10 is alive with NED for 18 months. In contrast to the other patients of this group, this patient had a tumor extension limited to the ipsilateral chest wall and was in good general condition. This led to the decision to retreat her with HT and conventionally fractionated re-RT. In Group C (macroscopic recurrence 3-4 weeks after primary radical surgery) patient No. 6 achieved a CR and has been locally controlled for 16 months, with NED. Patient No. 7 has just finished the treatment.
In Group D (unresectable RAASB recurrences) patient No. 8 did not respond to HT/re-RT and died after 1 month. Patient No. 9 achieved a PR with good palliative effect and survived for 7 months. The clinical situation is presented in Figure 5A,B. Patient No. 10 is alive with NED for 18 months. In contrast to the other patients of this group, this patient had a tumor extension limited to the ipsilateral chest wall and was in good general condition. This led to the decision to retreat her with HT and conventionally fractionated re-RT.

Toxicity
Acute and chronic toxicity, according to CTCAE v5.0, are presented in Table 4. Acute toxicity occurred in nine out of 10 patients, with patients presenting with erythema grade 1 (n = 7), and hyperpigmentation grade 1 (n = 6), respectively. No thermal skin damage was observed by any of the 10 patients. Chronic grade 1 toxicity occurred in two patients: Patient No. 4 who received four series of HT/re-RT (with partially overlapping treatment fields) showed hyperpigmentation and extensive new telangiectasia ( Figure 4L), and patient No. 10 who developed distinct hyperpigmentation.

Toxicity
Acute and chronic toxicity, according to CTCAE v5.0, are presented in Table 4. Acute toxicity occurred in nine out of 10 patients, with patients presenting with erythema grade 1 (n = 7), and hyperpigmentation grade 1 (n = 6), respectively. No thermal skin damage was observed by any of the 10 patients. Chronic grade 1 toxicity occurred in two patients: Patient No. 4 who received four series of HT/re-RT (with partially overlapping treatment fields) showed hyperpigmentation and extensive new telangiectasia ( Figure 4L), and patient No. 10 who developed distinct hyperpigmentation.

Chronic side effects
Acute and chronic side effects are indicated according to CTCAE grading. * = new telangiectases after 4 series of re-RT/HT with 5 × 4 Gy 1×/week, mainly in mechanically charged skin parts. No thermal related skin damage, e.g., blisters, has been noted. Grade 1 (G1) toxicity was handled with usual topical skin treatment.

Discussion
Given the low incidence of RAASB, there is no standard of care, especially regarding adjuvant therapies. For the outcome of initial RAASB treatment, quality and extent of surgery seem to be decisive. Management of the disease in specialized centers may significantly improve outcome [32]. Larger surgical margins are associated with improved survival [5,11,33]. Radical surgery, including resection of all pre-irradiated skin areas, followed by flap reconstructions can significantly decrease the risk of LR, and can lead to exceptionally high OS rates [2,10,11]. However, radical surgery is associated with a signi-ficant increase in postoperative complication rates compared to a more conservative skin resection [11]. In individual cases, the mutilation due to the resection of large skin areas followed by flap reconstruction, must be weighed against limited medical operability of older patients as well as the individual demand of the patient [34]. Pre-clinical and first clinical data on the use of targeted therapies and immunotherapy in the treatment of angiosarcoma have extensively been discussed by Cao et al. [35].
Data on the efficacy of adjuvant and neoadjuvant chemotherapy (CT) as well as adjuvant RT in the treatment of first RAASB manifestation are inconsistent [5,36]. Some authors deny the need for adjuvant RT by presenting good local control rates after radical surgery alone [5,10,11], whereas other authors emphasize the high risk of local recurrence [14,20]. The risk of RAASB recurrence might be caused by wide-spread and occult microscopic metastases within the skin, extending from the macroscopic tumor.
There is a comprehensible reluctance of applying RT to a tumor with radiation-induced etiology. In one multivariate analysis of a populations-based study, adjuvant RT seemed to be associated with worse OS [13]. In contrast, no impact on OS, but significantly better RFS, was found in systematic literature reviews [7,9]. Several authors state that their data do not allow for any recommendation pro or contra adjuvant RT (e.g., [6]).
Smith et al. [20] applied hyperfractionated, accelerated radiotherapy (HART) with atypically generous radiation field margins of 5-10 cm, pre-or postoperatively. They reported a median OS of 7 years, and a 5-year OS of 79%. Notably, surgery was included whenever feasible, with the resection of all pre-irradiated tissues [20]. Efficacy of this method was confirmed by observations of Donovan et al. [37].
The two patients in our cohort who received adjuvant re-RT/HT after mastectomy of initial RAASB (group A) did not undergo radical surgery including all pre-irradiated skin. Nevertheless, they showed local control (LC) for 37 and 67 months respectively, despite the fact that the latter patient had an R2 resection. In contrast to the review by Dogan et al. [8], this patient can be presented as a long-term survivor despite incomplete tumor resection. Thus, based on this limited and only single institutional experience, we would recommend adjuvant re-RT/HT, at least for cases where radical surgery is not possible or is refused.
Regarding local recurrences of RAASB as well as unresectable RAASB, limited data on treatment options and prognoses are available.
Standard treatment of locally recurrent RAASB is again surgical intervention with curative intent, whenever feasible. However, the rate of re-recurrences is high [5,15], often developing within a short period of time. Li et al. [11] report a median interval from first to second local recurrence of just 4 months. In contrast to the first RAASB resection, radical salvage surgery of recurrences did not significantly increase disease-specific survival [11].
In both first manifestations and recurrences of RAASB, prognosis is poor if R0 resection cannot be achieved [14]. Consequently, the same applies for unresectable RAASB. In a systematic review, long-term survivors were only found in cases of complete tumor resection [8].
De Jong et al. [21] and Linthorst et al. [22] reported their results of combined HT/re-RT for RAASB. Similar to our analysis, in both retrospective studies the percentage of patients with recurrent or unresectable disease was far above average compared to other singleinstitution reviews. The AMC protocol followed in Amsterdam consisted of a total dose of 32 Gy (8 × 4 Gy, 2×/week) combined with HT using a 434 MHz microwave technique given once per week within 1 h after RT [21]. Among 16 patients in AMC Amsterdam, 2 were unresectable, 12 were locally recurrent, and only 2 received combined adjuvant HT/re-RT after first resection. Complete response rate of macroscopic disease was 58%. Four of thirteen (31%) patients who were treated for macroscopic disease had good local control until either death or last follow-up (at 5, 7, 11, and 39 months) [21].
Of 23 patients at Erasmus MC Rotterdam, total RT doses ranged between 32 to 54 Gy (mean: 35 Gy) followed by HT either once a week for a total of four sessions or twice a week for a total of six sessions. HT was performed using 434 MHz microwave technique. Twelve patients presented with unresectable macroscopic disease. Complete response rate was 56%, and the 3-month, 1-and 3-year LC rates were 54%, 32%, and 22%, respectively. Eleven patients received adjuvant HT/re-RT after surgery, four with R0, six with R1, and one with R2 resection. Three-year LC rate was 46%. Late grade 4 RT toxicity was seen in two patients. One developed osteoradionecrosis of the chest wall requiring resection of the necrotic area, and the other required debridement for a chronic wound [22]. Molitoris et al. [38] published a case report on the treatment of a locally recurrent RAASB using a novel treatment intensification strategy including neoadjuvant HART with concurrent HT, followed by total mastectomy and flap reconstruction.
Our data are in complete agreement with the aforementioned data on beneficial effects of combined HT/re-RT in the treatment of recurrent and unresectable RAASB. Among three patients treated with adjuvant HT/re-RT after resection of recurrent RAASB (group B), one patient remained locally controlled during lifetime (R0 resection), and the other two patients who had an R1 resection, experienced a local recurrence. One of these two patients developed several re-recurrences, which could always be re-treated with the same schedule, leading to transient complete responses. The first local recurrence was in-field, and the others grew around the borders or out-of-field despite initial adequate RT-and HT-volumes (with margins of >5 cm up to 10 cm of all visible lesions). In contrast to our data on adjuvant re-RT/HT after surgery of first RAASB, re-recurrences following HT/re-RT after surgery of recurrent RAASB arise the question of higher adjuvant re-RT doses. However, intensification of re-RT dose is likely to be limited in such situations due to the presence of critical skin conditions. For example, patients No. 3 and 4 had skin transplantation applied on an already irradiated tissue (mesh graft, see Figures 3E and 4B), therefore were at risk for critical toxicities of pre-irradiated or grafted tissue. Notably, none of the patients died from local progression. Even if no long-lasting LC was achieved, we have shown that this schedule can be used repeatedly, and is able to induce short-lasting CR, making this schedule a good palliative treatment option.
In cases of immediate macroscopic recurrence after surgery and refusal of another resection (group C), combined HT/re-RT can be utilized. The aforementioned data from the Netherlands, and the positive experience with patient No. 6 supports this.
The same applies for the palliative treatment of unresectable RAASB (group D). One heavily pretreated patient with extremely limited life expectancy did not respond to the treatment, however another patient with a large-sized RAASB achieved partial remission (PR) and good palliative effect. A patient with general good, condition despite an unresectable tumor, achieved a CR with local control (FU time 18 months). It is noteworthy that due to her excellent performance status, a standard fractionation with a semi-curative total dose was chosen.
The low acute and chronic toxicity rates upon a total re-RT dose of 20 Gy in five fractions (once weekly) may alleviate concerns of unacceptable toxicity of re-RT of RAASB. In fact, toxicity was low enough that even with repeat HT/re-RT with a time interval of only a few months, treatment could safely be delivered. In addition, the patient-friendly course of five weekly treatment sessions ensures a high compliance.
Note: Benign skin alterations, listed in detail in Table 2, also merit comment. In particular, the role of vascular degenerative changes, e.g., telangiectases (TA) and ruby points (cherry hemangioma) remain unclear in the development of RAASB. The incidence of TA has often been associated with RT-techniques, especially with the use of electrons ≥15 MeV. However, there are also dose-independent genetic risk factors as evidenced by the association of the XRCC1 (R399Q) DNA repair gene polymorphism with increased risk of telangiectases irrespective of the patient having received a boost [39]. Interestingly, our patients presented with TA outside of the former boost field in the remaining, previously irradiated skin post-mastectomy. This could support the hypothesis of additional gene factors. This observation is in agreement with Fodor et al. [40], who described post-RT related grade 2 TA in two out of eight patients. Brenn and Fletcher [41,42] associated TA with other post-radiation atypical vascular lesions (AVL) as a possible morphologic continuum in the development of cutaneous angiosarcoma. However, a clear correlation is missing, due to the small number of described cases. Ashack et al. [43] did not find any correlation of late RT-sequelae of skin and RAASB. Fair hair and skin color had been associated with the incidence of radiation induced basal cell carcinoma [44] but to our knowledge, it has never been as an important factor with regard to RAASB. Despite the occurrence of RAASB in our patients with fair hair, skin type I or II, the understanding of possible correlations is poor, due to the low number of patients. Banks et al. [45] reported skin fibrosis after previous RT in 19/56 patients. In our study 5 out of 10 patients presented with ruby points (cherry hemangiomas), and 2 with fibrosis of the remaining skin after mastectomy of RAASB. Another two patients had severe postoperative complications after breast conservation before the onset of RT (Table 1), but the fibrotic tissue was removed during the mastectomy. Based on these rare observations it is too early to give any recommendations to radiation oncologists for how to take care of AVLs at the onset of first RT of breast cancer. Nevertheless, we suggest noting cherry hemangiomas and other clinical observations in future prospective studies.

Conclusions and Outlook
Given the poor prognosis and limited treatment options in cases of recurrent or unresectable RAASB, our data and reports from the Netherlands suggest combined HT/re-RT as a beneficial palliative treatment option. In addition, combined HT/re-RT should be considered as an adjuvant treatment of RAASB when radical surgery, including all pre-irradiated skin areas, is not feasible. Low toxicity rates using thermography-controlled, contactless wIRA-hyperthermia immediately followed by hypofractionated re-RT (5 × 4 Gy treatments delivered once a week) allows for repeat re-irradiations in case of re-recurrences. The applied wIRA-hyperthermia method seems to be a good technical solution for heating RAASB patients, because it produces very large treatment fields. In addition, most of these tumors occur within the first 5 mm from the surface and can thus be heated adequately.
Prospective data on the use of combined HT/re-RT and corresponding multi-center studies are required. Institutional Review Board Statement: Ethical review and approval were waived for this study, due to its retrospective analysis of standard routine use.
Informed Consent Statement: Informed consent was obtained from all patients involved in the study to publish this paper.
Data Availability Statement: Data supporting reported results are in the archives of the hospital and not available for any outside institution due to legal regulations. In addition, anonymous data of the patients are saved in cantonal or federal cancer registries, but again not available publicly.

Conflicts of Interest:
The authors declare no conflict of interest.
Abbreviations RAASB = radiation associated angiosarcoma of the breast LRBC = locally recurrent breast cancer RT = radiotherapy re-RT = re-irradiation HART = hypofractionated accelerated radiotherapy wIRA = water filtered infrared-A HT = hyperthermia CT = chemotherapy H = hormone therapy S = surgery OS = overall survival LR = local recurrence LRR = local recurrence rate RFS = recurrence-free survival FU = follow up LFU = lost to follow-up CR = complete remission PR = partial remission SD = stable disease PD = progressive disease LC = local control NED = no evidence of disease TA = telangiectases AVL = atypical vascular lesions Dx = diagnosis TM = total mastectomy Cobalt-60 = radiation unit using 60 Co sources