[Abstract] Objective To evaluate the value of intraoperative electron beam radiation therapy technique in limb preservation surgery for periarticular bone and soft tissue malignant tumors of the limbs. Methods Between October 2008 and April 2012, 19 patients with malignant tumors of bone and soft tissue around limb joints were treated with intraoperative electron beam radiotherapy combined with limb-sparing surgery, including 8 patients with tumors around knee joint, 6 patients with tumors around hip joint, 4 patients with tumors around elbow joint, and 1 patient with tumors around shoulder joint. All patients underwent limb-preserving surgery, including 18 cases of R0 resection and 1 case of R1 resection. The intraoperative irradiation dose ranged from 10 to 22 Gy, with a median of 19 Gy. Nine cases were irradiated with single field, and 10 cases were irradiated with multiple fields. Among the 19 patients in the group, 7 (36.8%) had poor wound healing, infection and subcutaneous effusion, and no acute radiation injury of grade III or higher. 1 (5.3%) patient developed a radioactive ulcer 15 months after surgery, forming an arterial fistula and undergoing emergency amputation. The limb function score for the whole group was (26.26±4.04) according to the 1993 American Academy of Bone Oncology scoring system, and the overall excellent rate of joint function was 94.7% (18/19). 4 patients (21.1%) had local recurrence, and the local control rates at 1, 2 and 3 years were 81.9%, 73.7% and 73.7% for the whole group, respectively. 7 patients (36.8%) died. Seven patients (36.8%) died, and the 1-, 2-, and 3-year survival rates for the whole group were 76.3%, 61.2%, and 51.0%, respectively. Conclusion The application of intraoperative electron beam radiation therapy combined with limb preservation surgery for the treatment of periarticular bone and soft tissue malignant tumors in the limbs is associated with milder acute and chronic toxic side effects, higher clinical safety, higher local control rate of tumors, and preservation of limb and joint function as much as possible, which improves the quality of life of patients. [Subject matter] Bone tumor; soft tissue tumor; joint; intraoperative radiation therapy The periarticular area of the limb is a common site for the occurrence of bone and soft tissue tumors. Due to the special location and anatomical structure of the periarticular area of the limb, malignant tumors located in this area are more difficult to handle, and the resection range of the tumor is often relatively limited, thus there is a potential high risk of local recurrence, and some patients even face the risk of amputation [1-2]. In the past, clinicians often compensated by postoperative adjuvant radiation therapy to improve the local control rate and increase the chance of limb-preserving treatment. However, for periarticular tumors, postoperative radiation therapy has certain limitations. In recent years, a new intraoperative electron beam radiation therapy technique (Mobetron intraoperative radiation therapy technique) has gradually started to be used in clinical practice [3]. It not only can precisely locate the tumor bed and the area to be irradiated, but also has its own advantages of electron ray irradiation, which can maximize the protection of normal tissues from or minimize unnecessary irradiation and reduce the side effects of radiation therapy. In this study, we retrospectively analyzed the clinical data and treatment effects of 19 patients with malignant tumors of bone and soft tissue around limb joints who underwent intraoperative electron beam radiation therapy combined with limb preservation surgery in our hospital between October 2008 and April 2012. Data and methods 1. Clinical data: Between October 2008 and April 2012, 19 patients with malignant tumors of bone and soft tissues around limb joints who underwent intraoperative electron radiation therapy combined with limb-preserving surgery in Cancer Hospital of Chinese Academy of Medical Sciences, including 9 men and 10 women; age ranged from 17 to 80 years old, with an average age of 52.3 years. The tumors were located around the knee joint in 8 cases; around the hip joint in 6 cases; around the elbow joint in 4 cases; around the shoulder joint in 1 case. The tumor diameter ranged from 3 to 20 cm, including 17 cases with tumor diameter ≥5 cm and 9 cases with tumor diameter ≥10 cm. There were 14 cases with single tumor and 5 cases with multiple tumors. Referring to the 2010 American Joint Committee on Cancer 7th edition TNM staging criteria [4] for staging, there were 2 cases of stage I, 3 cases of stage II, 12 cases of stage III, and 2 cases of stage IV (1 case of postoperative distal humeral metastasis from renal clear cell carcinoma; 1 case of suspected pulmonary metastasis at the time of surgery, and the primary tumor was huge and about to collapse). There were 5 cases of bone tumors, including 4 cases of primary tumors (3 cases of osteosarcoma and 1 case of chondrosarcoma) and 1 case of metastatic tumor (distal metastasis to the humerus after renal clear cell carcinoma); 14 cases of soft tissue tumors, including 3 cases of synovial sarcoma, 2 cases of malignant peripheral nerve sheath tumor, 2 cases of fibrosarcoma, 2 cases of smooth muscle sarcoma, 1 case of malignant fibrous histiocytoma, 1 case of undifferentiated high-grade pleomorphic sarcoma, 1 case of liposarcoma 1 case of soft tissue clear cell sarcoma, 1 case of small round cell malignant tumor. 2. Preoperative treatment: Among the 19 patients, 10 patients had recurrence after external surgery (5 cases had 1 surgery, 3 cases had 2 surgeries, 2 cases had 3 surgeries), 2 cases had further extensive resection after external unplanned resection, and 7 cases had initial treatment in our hospital. 3 patients had received previous radiation therapy, of which the radiation dose of 2 patients was 65 Gy and the specific dose of 1 case was unknown. 3 patients had received preoperative Three patients had received chemotherapy before surgery, with 2 to 4 cycles of chemotherapy, with an average of 3 cycles. 3. Surgical treatment: All patients underwent limb-preserving surgery. The tumor resection method was R0 resection (no tumor remains under the naked eye and microscope) in 18 cases; R1 resection (no tumor remains under the naked eye, but tumor remains under the microscope) in 1 case. There were 5 cases of combined resection of important structures, including 1 case of combined tibial nerve + N artery resection, 1 case of tibial nerve + N vein resection, 1 case of pubic branch resection, 1 case of partial iliac bone resection, and 1 case of partial humerus resection. The repair and reconstruction methods were flap or myocutaneous flap displacement repair in 5 cases (2 cases of thoracic umbilical flap displacement, 2 cases of rectus abdominis muscle flap displacement, and 1 case of large collecting muscle penetrating flap displacement), artificial tumor knee joint replacement in 4 cases, artificial tumor elbow joint replacement in 1 case, allograft bone implantation + intramedullary pin and plate internal fixation in 1 case, and artificial blood vessel replacement in 1 case. 4. Intraoperative radiotherapy: All patients had obtained pathological diagnosis before surgery, and intraoperative radiotherapy was performed in the operating room directly after completion of extensive tumor resection or tumor resection using the Mobetron 1000 movable intraoperative radiotherapy-specific electron wire linear gas pedal from Intraop, USA. The intraoperative radiotherapy modality and dose are decided by the radiologist and surgeon according to the pathological type, size, depth and stage of the tumor and whether to combine with postoperative extracorporeal irradiation. According to the required depth of irradiation, different electron beam energy was used for irradiation, including 6 cases of 6 Mev electron beam and 13 cases of 9 Mev electron beam. According to the size of the tumor and the angle of irradiation, different diameter and angle of tilt were used to limit the light cylinder, with a diameter of 6-10 cm and an angle of tilt of 0°-30°. Due to the large size of the tumor and the maximum diameter of the limiting cylinder was only 10 cm, except for 9 patients who were irradiated with single field, the other 10 patients were irradiated with multiple fields, including 4 cases with 2-field irradiation, 3 cases with 3-field irradiation and 3 cases with 4-field irradiation. The dose of irradiation ranged from 10 to 22 Gy, with a median dose of 19 Gy. 5. Postoperative adjuvant therapy: one case was treated with postoperative supplemental external irradiation at a dose of 50 Gy. Four cases were treated with adjuvant chemotherapy for 2 to 3 cycles, with anthracyclines, platinum, isocyclophosphamide, methotrexate and azulfiram. 6. adverse reactions and evaluation of limb and joint function: patients were evaluated for adverse reactions after radiotherapy with reference to the Radiation Therapy Oncology Collaborative Group-European Organization for Research and Treatment of Oncology (RTOG-EORTC) grading criteria for acute and chronic radiation injury [5]. Late adverse reactions were defined as first symptoms occurring 3 months after intraoperative electron beam radiation therapy or symptoms persisting for more than 3 months after completion of treatment [5]. Patients’ post-treatment limb joint function was evaluated with reference to the 1993 American Academy of Bone Oncology scoring system [6]. 7. Follow-up: Patients were followed up by outpatient review or by telephone, and the follow-up was conducted until April 30, 2012. All 19 patients in the group were followed up, and the follow-up rate was 100%. The follow-up time ranged from 1 to 42 months, with a median follow-up time of 17 months. 8. Statistical methods: SPSS 19.0 statistical software was used for statistical analysis, and the Kaplan-Meier method was used to calculate the local recurrence rate and survival rate, etc., and the Log rank significance test was performed. The test level was α=0.05. RESULTS 1. Occurrence of complications and adverse reactions: (1) Recent: Among the 19 patients in the whole group, there were 7 cases (36.8%) of poor wound healing, infection and subcutaneous effusion, and 1 case (5.3%) of hemorrhagic shock. None of the patients in the whole group had acute radiation injury of grade III or above. (2) Late stage: 1 case (5.3%) developed radioactive ulcer, formed arterial fistula, wound infection and hemorrhagic shock 15 months after surgery, which belonged to grade IV skin and subcutaneous tissue late radiation injury, and emergency amputation was performed. 2. Results of limb and joint function evaluation: The postoperative limb and joint function scores of the whole group of patients ranged from 15 to 30 (50% to 100%), with an average of (26.26±4.04) points (87.5%±13.5%). The overall excellent rate of limb and joint function was 94.7% (18/19). 3. Local recurrence and distant metastasis: 4 patients (21.1%) in the whole group had local recurrence after surgery. The local control rates at 1, 2 and 3 years were 81.9%, 73.7% and 73.7%, respectively. 9 patients (47.4%) had distant metastases, including lung, mediastinum, brain and soft tissue. 4. Survival: By the end of follow-up, 7 patients (36.8%) died in the whole group, and the 1-, 2- and 3-year survival rates of the whole group were 76.3%, 61.2% and 51.0%, respectively. Discussion The large joints of the limb are the parts of the limb that connect the bones to each other, mainly including the hip, knee, ankle, shoulder, elbow, and wrist joints, which are important parts of the limb for various activities such as flexion, extension, and rotation, and are important and basic units of the body for daily activities [1-2]. The anatomical structure around the limb joints is complex, as it is the confluence of important muscles and tendons, as well as the location of important blood vessels and nerves. The treatment of malignant tumors around limb joints is more difficult. After resection of tumor in this area, in order to preserve the function of limb, it often involves repair and reconstruction of joint or soft tissue. For example, joint function reconstruction after bone tumor segment amputation, artificial joint prosthesis replacement, allogeneic bone graft, inactivated bone replantation of tumor segment, autologous bone graft with blood vessels, etc.; soft tissue tumor resection with vascular tip or free skin flap or myocutaneous flap transfer coverage, etc.; also may involve repair and reconstruction of blood vessels or nerves (such as blood vessel replacement, blood vessel graft and nerve graft, etc.). Among the 19 patients in this group, there were 5 cases of flap or myocutaneous flap displacement; 5 cases of joint replacement, 1 case of allograft bone implantation and internal fixation, and 1 case of artificial vascular replacement. Periarticular malignant tumors are often located outside the interstitial space, lacking a natural barrier, and are extra-interstitial tumors in the surgical staging system of tumors, and the tumor tissue can easily spread in all directions along neurovascular gaps or tissue gaps, etc [1]. Therefore, extensive resection should be performed for such tumors. However, for periarticular malignant tumors, conventional surgical approaches (such as wide resection or intercompartmental resection) are often difficult to achieve due to the limitations of important blood vessels, nerves and muscles and tendons, etc.; and the huge destruction caused by wide resection is almost impossible or difficult to repair, which may result in serious impairment of limb joint function or even limb joint non-function. Therefore, periarticular bone and soft tissue malignant tumors can often only be resected marginally or even intracapsularly, which leads to a potentially high risk of local recurrence. Once the periarticular tumor is not properly controlled locally, it often leads to serious limb dysfunction and even risk of amputation. Therefore, adjuvant therapies in the perioperative period play an important role in the local control of periarticular malignancies, of which radiation therapy is an effective and important adjuvant treatment [7]. In the past, postoperative adjuvant radiotherapy was often used to improve the local control rate after limb tumor resection. However, for periarticular tumors, postoperative radiotherapy has certain limitations: (1) when joint function reconstruction is involved, such as after artificial joint prosthesis replacement, allogeneic bone grafting, inactivated bone replantation of tumor segments, and autologous bone grafting with blood vessels, postoperative radiotherapy may lead to severe osteolysis or bone destruction, which can be devastating to the reconstructed joint function. Therefore, postoperative radiotherapy is almost impossible to achieve for patients with joint reconstruction. (2) When soft tissue repair is involved, such as after transfer coverage with a vascular-tipped or free flap or myocutaneous flap, the healing time of the wound is often long, resulting in the inability to perform postoperative radiotherapy in a timely manner, thus affecting the effectiveness of postoperative radiotherapy [8]. (3) The localization of the tumor bed by postoperative radiotherapy is not precise enough and the irradiation range is large, which may lead to extensive fibrosis around the joint and will seriously affect the joint function or even lead to non-functional joint. In addition, irradiation needs to reach the tumor bed through the skin and subcutaneous tissues, which will lead to poor subcutaneous lymphatic drainage system and venous return system, causing severe edema in the distal limb [9], further aggravating the dysfunction of limb joints. Intraoperative electron beam radiation therapy can precisely locate the target area, effectively protect the surrounding normal tissues, and minimize the toxic side effects of radiotherapy. In this study, we used intraoperative electron beam radiation therapy technique combined with limb preservation surgery to treat patients with peri-articular tumors of the limb in order to improve the therapeutic effect of the tumor, improve joint function, and thus improve the survival quality of patients. The results of this study showed that the incidence of wound complications was high in the whole group of patients, at 36.8%. The reasons for this may be related to the fact that the surgery of periarticular tumors is more complicated, more traumatic, and mostly requires repair and reconstructive surgery. In contrast, the incidence of wound complications in patients in the non-periarticular group during the same period was 6.7% (1/15), which was lower than the results reported in the literature [7,9-11].The results of a study by Kunos et al [12] showed that the use of intraoperative electron beam radiation therapy combined with limb-preserving surgery for soft tissue sarcoma of the limb did not significantly increase the incidence of acute and chronic toxic side effects in patients. One patient in our group who also underwent tibial nerve resection developed a radiological ulcer and formed an arteriovenous fistula 15 months after surgery, which was considered to be related to late radiation damage (destruction of the smooth muscle layer of blood vessels) from intraoperative radiotherapy [8]. However, it remains to be further investigated whether local loss of innervation of blood vessels or surrounding tissues may promote the development of radioactive ulcers. The postoperative joint function of the limbs in this group of patients was relatively satisfactory, with an excellent rate of (94.7%). This may be related to the more precise positioning of intraoperative electron beam radiotherapy, relatively small irradiation area, and greater reduction of fibrosis in periarticular, skin and subcutaneous tissues. The local control rate of our patients was satisfactory, with local control rates of 81.9%, 73.7% and 73.7% at 1, 2 and 3 years, respectively, similar to the results reported in the literature [7,9-11]. However, the incidence of distant metastases and mortality were not satisfactory, which may be related to the fact that most of the patients in this group were recurrent patients, with advanced disease stage and large tumor size.Skandarajah et al [13] found through a literature review that intraoperative radiotherapy can significantly improve the local control rate in patients with solid tumors, but may not improve the overall survival of patients. In this study, we divided the patients into the intraoperative radiotherapy-only group and the postoperative supplemental radiotherapy group according to whether they were treated with postoperative extracorporeal radiotherapy or not. For patients treated with intraoperative radiotherapy alone, we used a stepwise gradual increase in radiation dose from 10 Gy to 20 Gy in the first 8 patients, taking into account the possible serious adverse effects of radiation on joint cavities and important blood vessels, etc. Since the increase in radiation dose within this dose range did not significantly increase the recent complications. Therefore, the radiation dose was increased to 20 Cy in all patients afterwards, and only one patient with 20 Gy radiation therapy has experienced local recurrence since the follow-up. In the postoperative supplemental radiotherapy group, three patients were proposed to be treated with postoperative adjuvant radiotherapy with an intraoperative radiation dose of 10-13 Gy. However, due to the relatively high postoperative complications of periarticular tumors, only one patient successfully completed postoperative adjuvant radiotherapy, and the other two developed subcutaneous effusion in the postoperative wound, which delayed the treatment time and eventually abandoned further postoperative radiotherapy. Therefore, for periarticular malignant tumors, we believe that the more appropriate intraoperative radiation dose is 20 Gy at present and do not recommend postoperative supplemental external radiotherapy for the time being. Whether it is necessary to further increase the intraoperative radiation dose remains to be further studied. In addition, due to the relatively large size of bone or soft tissue malignant tumors, and the maximum diameter of the Mobetron 1000 electron linear gas pedal limiting cylinder is only 10 cm, some patients need to use multiple irradiation techniques in multiple fields, and the irradiation process is relatively complicated. The irradiation area is divided into several fields according to the shape of the limiting cylinder, and the boundaries between the fields are marked with sutures. The junction area between the irradiated fields must be strictly noted during the irradiation process, and the lead block and the marked sutures must be clearly blocked from the top of the light-limiting cylinder again before irradiation to avoid repeated irradiation or missed irradiation of the junction area of the irradiated fields. In summary, we applied intraoperative electron beam radiation therapy technique to limb-preserving surgery for periarticular malignancies, and the results showed that intraoperative electron beam radiation therapy can significantly increase the local control rate of tumors, reduce the incidence of joint complications, improve limb function, and improve the quality of life of patients, and the therapeutic effect is gratifying. However, whether intraoperative electron beam radiation therapy can significantly improve the survival rate of patients remains to be further studied.