Neoadjuvant concurrent chemoradiotherapy with and without hyperthermia in retroperitoneal and intra-abdominal sarcomas: Feasibility, ecacy, toxicity and long-term outcome

Background Retroperitoneal (RPS) and intra-abdominal sarcomas (IAS) are associated with poor local and abdominal tumor control. Yet, the benet of preoperative radio- or chemotherapy alone for these entities currently is unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency for early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. Methods From 2000-2019, 27 patients with intermediate- or high-grade RPS or IAS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50mg/m² BSA/d3 q28 and ifosfamide 1.5g/m2 BSA/d1-5 q28) in neoadjuvant intention. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) received deep regional hyperthermia additionally. Results The median follow-up time was 53 months (± 56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free-survival was 74.6% (± 10.1%) and 66.3% (± 11.9%), distant-metastasis-free-survival was 67.2% (± 9.7%) and 59.7% (± 11.1%), and overall-survival was 60.3% (± 10.5%) and 60.3% (± 10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%) and anemia (11%). There were no treatment-related deaths.


Background
Retroperitoneal sarcoma (RPS) and intra-abdominal sarcomas (IAS) are rare and challenging oncologic entities. Liposarcoma and leiomyosarcoma are the main histologic types encountered, with high-grade histology being present in half of all cases (1-3). Although surgical resection is the mainstay of treatment for cases without distant metastasis, most patients ultimately develop intra-abdominal recurrences after resection alone (4), which is the rationale for additive radiation treatment (RT). Retrospective case series results suggest that postoperative radiotherapy (PORT) may provide increase local tumor control (5-7).
There are, however, limitations for the implementation of PORT, such as problems in de ning the postoperative volume to be irradiated after resection and the risk of higher long-term gastrointestinal toxicity, as abdominal organs settle back into their regular positions after surgery (8). On the other hand, preoperative radiotherapy has the advantage of a more straightforward de nition of the clinical target volume and the reduction of late side effects in patients with soft-tissue sarcoma of the limbs (9). The EORTC-STRASS trial investigated the bene ts of preoperative radiotherapy for RPS and showed that neoadjuvant radiotherapy is well-tolerated but does not improve abdominal-recurrence-free-survival (AFRS) (10). Subgroup analyses revealed that preoperative radiotherapy signi cantly improved AFRS in low-grade sarcoma and liposarcoma, but not in high-and intermediate-grade sarcoma, suggesting that the different grades of RPS require a differentiated treatment approach according to tumor grade.
These ndings raise the important question whether the addition of chemotherapy (CT) and hyperthermia (HT) to radiotherapy might result in improvement of intra-abdominal control rates. To explore this question, this retrospective analysis was designed to treatment outcome of RPS and IAS patients who received combined chemoradiotherapy (CRT) at the Department of Radiation Oncology, University Hospital of Erlangen. In recent years, neoadjuvant concurrent chemoradiotherapy (CCRT) has been expanded to additionally include hyperthermia in selected cases (11).

Patient characteristics:
All data on the course of disease and follow-up of all sarcoma cases entered in our hospital database since 2000 were retrospectively evaluated (see Table 1). The cut-off date for analysis was August 31 st , 2019. The management of each case was discussed primarily in a multidisciplinary team setting before and after treatment, informed consent was obtained from all participants. According to the protocol, biopsy followed by neoadjuvant concurrent chemoradiotherapy was performed in all cases with con rmed FNCLCC grade G2 or G3 tumors. Neoadjuvant chemotherapy alone was not performed.
Exclusion criteria for neoadjuvant CCRT were ECOG >1, intestinal passage obstruction and/or age ³ 80 years. Patients with a high risk of severe renal failure following radiotherapy with or without subsequent nephrectomy were also excluded. This was determined by MAG3 scans (isotope nephrography) for the individual assessment of left and right renal function. Histological diagnosis was based on the World Health Organization (WHO) classi cation of soft tissue tumors valid at initial biopsy diagnosis. Tumor grading was performed according to the French grading system (FNCLCC).

Radiotherapy
The radiation techniques used were multi-eld 3D RT with a dose prescribed to the ICRU50 reference point until 2012, and intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) in subsequent years. Doses were generally delivered in fractions of 1.8 Gy, ve times a week. However, three patients received fractions of 1.5 Gy instead. Four patients treated before 2010 had a treatment protocol specifying a seven-day treatment break in week 3 (see Figure 1).

Chemotherapy
Twenty-four patients received a combination regimen of doxorubicin (50mg/m²/d on day 3) plus ifosfamide (1.5g/m²/d on days 1-5) in weeks 1 and 5 (if they had su cient cardiac and renal function) with appropriate antiemetic therapy (HT3 antagonist), hydration and cystitis prophylaxis. Three patients had comorbidities at baseline that required chemotherapy dose reduction. The rst cycle of chemotherapy was started in parallel with radiation. Granulocyte colony-stimulating factor (G-CSF) was not administered prophylactically but was given to patients with leukocytopenia (count < 1500/µL). To receive the second cycle of chemotherapy in week 5 of radiotherapy, patients had to have a leukocyte count greater than 3000/µL and a platelet count greater than 100,000/µL. If not, the second cycle was postponed by a maximum of 2 weeks or was not performed in case of inadequate restitution of hematopoiesis. Postoperative or consolidating chemotherapy was not performed in patients with inoperable disease.

Hyperthermia:
From 2004 on, regional hyperthermia was performed with a SD 2000 hyperthermia system (BSD Medical/Pyrexar, Salt Lake City, UT, USA) with or without non-invasive MR thermometry with 1-2 treatments/week. The target temperature was 40-44°C for 60 minutes per treatment.

Surgical resection:
En bloc resection of the tumor was to be carried out 6-10 weeks after the end of chemoradiotherapy if possible. The treatment regimen is illustrated in Figure 1. Additional pictures detailling the treatment regimen are shown in Figure 2.
Follow-up and statistics: The feasibility of chemotherapy was veri ed based on data in the patient treatment records and pharmacy records. The performance of radiotherapy was con rmed using the MOSAIQ Record & Verify System. Treatment toxicity was graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (12). Postoperative complications were assessed according to data in the electronic patient records. After the treatment, patients were scheduled for quarterly clinical and semi-annual computed tomography (CT) follow-up assessments. All patients without reported incidents were contacted by phone on the follow-up assessment date. Two patients were lost to follow-up. The data from their last clinical visits were included in the analysis.
Statistical analysis was performed using SPSS Statistics Version 26. Survival analysis was performed by means of the Kaplan-Meier method and the logrank test as well as Cox´s regression analysis. Differences of p<0.05 were de ned as statistically signi cant.

Patients:
Of the 27 patients included in the analysis, three ultimately received de nitive treatment because resectability was not archieved: persistent inoperability was con rmed by the multidisciplinary team based on the results of repeat imaging studies after the patients had received 50.4 Gy of radiation. Twenty-four patients were classi ed as potentially resectable and underwent surgery during the further course. Characteristics of the patient population are summarized in Table 1 Table 2).
Concomitant chemotherapy consisting of doxorubicin plus ifosfamide was administered to 24 patients. Of these patients, 7 (29%) received > 80% of the planned dose of ifosfamide, while 11 (46%) received >50% and 6 (25%) received 30%-50% of the total dose of 15g/m² of ifosfamide planned for the two cycles. For doxorubicin, 20 (83%) of the patients received more than 80% of the planned dose of 100mg/m² over two cycles, and the remaining four patients received 50% to 80% of the target dose.
Chemotherapy was administered according to protocol in 24 cases (89%).
Due to age > 80 years, two patients received weekly full-dose doxorubicin monotherapy for at least 5 cycles (to a total dose of 75mg/m²). In the remaining case, a patient pretreated with doxorubicin received ifosfamide parallel to radiotherapy at a dose of 1.5g/m²/d on days 1-5 but could not receive the second cycle due to severe deterioration of his general health.
Hyperthermia treatment (HT) was administered parallel to RCT in 15 (56%) patients, who received a median of 5 HT treatments.
Of the patients who received neoadjuvant therapy, 16 (67%) were classi ed as R0 after en-bloc resection (see Table 2), 6 (25%) as R1. The resection status of 2 (8%) could not be determined due to missing data at the time of the analysis.
Toxicity pro le: The most common adverse events of chemoradiotherapy were hematological side effects (see Table 3). Surgical resection could be performed at the planned time in all cases. The most common AEs were radiation dermatitis (19%, none CTCAE grade 3 or 4) and diarrhea (6%). Eight patients (26%) experienced nausea throughout the treatment. Postoperative complications were acute renal failure (n=1), burst abdomen (n=1), anastomotic leakage (n=1), and cerebellitis (n=1) 3 weeks after surgery. The case of cerebellitis was determined to be autoimmune and resolved spontaneously within a few weeks.
Page 7/24 E cacy: The rate of abdominal recurrence-free survival was 95.8% (± 4.1%) at one-year follow-up, 74.6% (±10.1%) at three years, 74.6% (±10.1%) at ve years, and 66.3% (±11.9%) at ten years (see Figure 3). Tumors <10cm vs. ≥ 10cm in diameter showed differences in the length of ARFS, yet they were not signi cant (p=0.076, univariate analysis). ARFS rates were slightly better in G2 tumors, compared to G3 tumors, in patients who received more than six hyperthermia treatment sessions and younger patients. Still, the differences were not signi cant (see Table 4). In multivariate Cox's regression analysis, none of the variables was found to be an independent prognostic factor but no conclusions should be drawn from this nding in view of the low number of events. In case of recurrence (n=15), the decision to perform chemotherapy (n=4), repeat chemoradiotherapy (n=1), radiotherapy (n=1), surgical resection (n=5) or palliative treatment (n=4) was made on a case-by-case basis. Local recurrence appeared in eld in 3 patients and out eld in 3 patients.
Distant-metastasis-free-survival (DMFS): Ten patients developed distant metastases, which initially occurred in the lungs in six cases, in the bone in three, and in the duodenum in one case. In 90% of cases, the metastases developed within 2 years of the start of treatment. The DMFS rate was 67.2% (±9.7%) at 3 years, 67.2% (±9.7%) at 5 years, and 59.7% (±11.1%) at 10 years. The difference in DMFS between recurrences and primary tumors was noticeable: 56% of patients with recurrent tumors developed further recurrences compared to 32% of those with primary tumors. In the case of DMFS, no independent predictors could be identi ed by multivariate analysis either in context of a low number of events. There was no difference in DMFS between patients with and without hyperthermia treatment.
Disease-free-survival (DFS): Disease-free survival was 48.1% (± 10.8%) at 3 years, 48.1% (± 10.8%) at 5 years, and 36.1% (± 11.0%) at 10 years. No confounding factors could be identi ed. Eleven patients received second-line therapy, consisting of surgery for recurrent disease in ve cases, radiotherapy in one case, and systemic therapy in ve cases. Four patients received palliative treatment.
Overall-survival (OS): On the cut-off date for analysis, 16 patients (59%) were still alive and 2 (7%) were lost to follow-up.
Overall survival was 70.4% (± 9.5%) at 3 years, 60.3% (± 10.5%) at 5 years, and 60.3% (± 10.5%) at 10 years (see Figure 4). Over the long term, women and patients with G2 tumors had better overall survival, but the difference was not signi cant. Recurrent disease patients who were diagnosed early enough that the recurrent tumors could be treated survived a median of 40 months.

Discussion
Concurrent chemoradiotherapy protocols combining chemotherapy with radiation treatment have now gained acceptance as modalities for treating a wide range of locally advanced solid tumors in the neoadjuvant setting (13)(14)(15). Intra-abdominal and retroperitoneal sarcomas pose similar challenges to surgeons regarding local resectability and recurrence rates after surgical resection alone. Nevertheless, neoadjuvant chemoradiotherapy is not a standard treatment for these tumor entities, especially after the negative results of the EORTC-STRASS study (10). We administer CCRT to patients with high-or intermediate-grade sarcomas on a case-by-case decision basis. Our experience is based on the treatment of sarcomas of the trunk and extremities. As early as 1999, Sauer et al. demonstrated in 22 patients initially classi ed as inoperable that secondary resectability could be achieved with neoadjuvant chemoradiotherapy (16). However, almost half of their patients developed high-grade toxicities, and one patient died (4%). Given the poor prognosis of sarcoma patients without resection, treatment toxicity was rated as acceptable because it achieved resectability. A later study of neoadjuvant CRT and surgery in 53 soft tissue sarcoma patients by Stubbe et al. resulted in a high long-term local recurrence rate of 90% (11) and one postoperative death (2%). Fourteen patients in their population had retroperitoneal sarcoma. The toxicity of treatment of RPS patients was not higher than that of patients with soft-tissue sarcoma of the extremities. Therefore, the concept was further established in the following years. We now report the results of the treatment of 27 cases of retroperitoneal and intra-abdominal sarcoma. This constitutes the most extensive published series of RPS/IAS patients treated with neoadjuvant concurrent chemoradiotherapy.
Our analysis of the data shows that the side effects of treatment are manageable, even when the combination of radiotherapy and chemotherapy is administered in a single-center setting directed by one department. Our treatment concept includes intensive supportive therapy with parenteral nutrition and antiemetic therapy as needed as well as early stimulation therapy in case of hematological toxicity. The ndings of the RTOG-9514 study highlight the importance of supportive treatment (17). Five percent of deaths observed in RTOG-9514 occurred in patients treated using a multicenter and multimodal approach. According to our analysis, hematological and gastrointestinal toxicities were the most critical factors, but they were well controlled by parenteral nutrition, and no increase in postoperative morbidity occurred.
Analysis of our population showed that neoadjuvant CCRT can achieve excellent local control of both surgically resected and inoperable RPS/IAS. Regarding the EORTC-STRASS study (10), the 5-year local control rate was 75% in the present study compared to only 47.6% in the EORTC-STRASS study. Moreover, our patient population had a less favorable prognosis as it was composed almost entirely of patients with high-or intermediate-grade tumors, whereas 34.6% of patients included in the STRASS study had low-grade sarcomas. Nevertheless, the bene t of neoadjuvant concurrent chemoradiotherapy must be evaluated in conjunction with the results of other studies. Data on this subject is sparse. For example, Gronchi et al. (18,19) achieved a local control rate of 63% with a neoadjuvant CCRT regimen consisting of radiotherapy up to a total dose of 50.4 Gy and high dose ifosfamide chemotherapy. Their treatment protocol was also feasible. They also included patients with low-grade RPS but required a minimum tumor size of 5 cm in diameter. The latter size speci cation was not always met in our study. Studies of neoadjuvant chemotherapy alone are also rare (20).
Encouraged by the ndings of Issels et al. (21), we administered hyperthermia treatment in addition to chemotherapy in almost half of our patients. In the end, we could not detect any signi cant difference between the patients who received hyperthermia and those who did not. This may be due to several factors. The main reason might be the small size of the sample, which resulted in reduced statistical power. Furthermore, it cannot be excluded that chemoradiotherapy alone might have already had a su cient local therapeutic effect. Finally, it can be concluded that hyperthermia did not result in increased toxicity, so adding regional hyperthermia to the regimen as described by Issels et al. (22) is not problematic.

Summary
In conclusion, the neoadjuvant concurrent chemoradiotherapy regimen established by us for selected retroperitoneal and intra-abdominal sarcoma patients is feasible and does not increase postoperative morbidity. In cases with and without surgical tumor resection, this approach achieved excellent local control rates, better than those obtained with radiotherapy alone. This constitutes an important signal that combined chemoradiation might be superior to radiotherapy alone in retroperitoneal and intraperitoneal sarcomas. The rate of distant metastasis of high-and intermediate-grade sarcomas remains high and needs further improvement.

Declarations
Ethics approval and consent to participate Each patient has agreed to the treatment and the subsequent use of the data for research purposes prior to the start of treatment in a separate treatment contract, which is available. Therefore, the Ethics Committee of the Friedrich-Alexander-University Erlangen-Nuremberg waived an additional approval on the use of data. Treatment and data collection had been performed in accordance with the Declaration of Helsinki.

Consent for publication
Informed consent was obtained from all participants or, if participants were under 18, from a parent and/or legal guardian.

Availability of data and materials
The datasets used and/or analysed during the current article are available from the corresponding author on reasonable request, please contact the corresponding author (Sabine.Semrau@uk-erlangen.de).
The authors declare that they do not have any competing interests.           Figure 1 Therapy regimen for neoadjuvant concurrent chemoradiotherapy ± hyperthermia in retroperitoneal and intra-abdominal sarcoma.

Figure 2
Page 23/24 Intra-abdominal liposarcoma with dose distribution of kidney-sparing radiotherapy (A), surgical site of enblock resection (B); strongly regressive altered residual tumor tissue after chemoradiotherapy (C) Overall survival in months