A pilot trial of high-dose-rate intraoperative radiation therapy for malignant pleural mesothelioma

PURPOSE: To report results of a phase II trial of high-dose-rate intra-operative radiation therapy (HDR-IORT) for malignant pleural mesothelioma (MPM). METHODS AND MATERIALS: Seven patients had extrapleural pneumonectomy with IORT (EPP/IORT) and 6 patients had pleurectomy/decortication with IORT (PD/IORT) between 1994 and 1996. IORT was delivered with 192Ir using a customized applicator with a remote afterloader. A median of 3 sites were treated to a median area of 143 cm2. A dose of 1500 cGy was prescribed at each site, with 1000 cGy delivered to the mediastinum. Postoperative external beam radiation therapy (EBRT) was given 3-5 weeks later. Median follow-up was 8 months (range, 1-84 months). RESULTS: Five patients developed local failure. Two-year local control and survival rates were 35% and 23%, respectively. Mortality was 2/13 (15%), 1 from each surgical group. Serious complications requiring further intervention occurred in 3/6 (50%) of the EPP/IORT group and 1/5 (20%) of the PD/IORT group. CONCLUSIONS: HDR-IORT after EPP for MPM is prohibitively toxic and has been abandoned, while its use with PD remains in question.     

Intraoperative Strahlentherapie (IORT) in der Behandlung des Mammakarzinoms – eine neue therapeutische Alternative im Rahmen der brusterhaltenden Therapie? Stellenwert und Zukunftsperspektiven. Erfahrungsbericht aus dem European Institute of Oncology (EIO), Mailand

BACKGROUND: External beam radiation therapy (EBRT) represents an integral component of breast-conserving treatment. In published series it has been demonstrated that the external boost can be replaced by intraoperative radiotherapy (IORT) where irradiation at a single dose from 10 up to 15 Gy was safely delivered directly to the tumor bed. PATIENTS AND METHODS: At the European Institute of Oncology, Milan, we initiated a dose escalation study to investigate the feasibility of applying single doses of IORT from 10 Gy up to 22 Gy. A portable IORT equipment with different electron energies was used. From July to December 1999, a total of 65 patients with T1-2 (max. 2.5 cm) No-1 breast cancer, median age 58 years (range 33-80 years) was treated. Ten patients received 10 Gy, eight patients were treated with an IORT of 15 Gy, eight received 17 Gy, six had 19 Gy, and 33 were treated with 21-22 Gy. Patients with 10 and 15 Gy received an additional EBRT of 44 and 40 Gy, respectively. In all other patients IORT was the sole radiation treatment. RESULTS: No acute side effects or intermediate untoward effects after a follow-up from three to nine months related to IORT were observed. CONCLUSIONS: Since the applicator can be safely placed under the control of the surgeon and radiotherapist IORT has the potential of accurately treating the tumor bed. Skin and subcutaneous tissue are not irradiated thus decreasing the potential risk of fibrosis and eventually obtaining a better cosmesis. With IORT single doses of 22 Gy being equivalent to a 60 Gy EBRT can safely be delivered. Even so the average time of operation was prolonged by around 20 minutes IORT application ultimately improves the quality of life of the patients in shortening overall treatment. Long-term follow-up is necessary to demonstrate whether large single doses of IORT might have the potential of sufficient local tumor control without major side effects. As a future perspective a randomized trial comparing EBRT with IORT as sole treatment will be performed.     

Intraoperative radiotherapy of upper abdominal tumours

Thirty patients with malignant tumours in the upper abdomen underwent surgery and intraoperalive radiation (IORT), using electron beam, to: the surgical bed, residual or unresected tumour. The technical aspects and results of this treatment are described. Renal, adrenal, bile duct and gastrointestinal tumours were treated. along with several other lesions. The surgical procedure consisted in 10 cases simply of exposure of the tumour for IORT and in 20 the tumour was resected. The TORT dose ranged from 10 to: 20 Gv. In 13 patients, external beam radiation was also given to: residual tumour or to: areas of high risk for recurrence. Chemotherapy was given to: 10 patients. Tolerance to: the combined treatment was acceptable; with few complications related to: IORT.The median follow-up and survival time 23 months (range 4-more than 70 months). Local tumour control rate (or tumour stabilisation) is 90%. Distant metastases developed in 19 patients (63%). The actuarial survival rate for the group projected at 70 months (maximum follow-up) is 37%. IORT in useful in the management of tumours arising in the upper abdominal organs, for palliation surgery or when resectability of the tumour is in doubt. Indications for IORT include patients with uncommon tumours of the upper abdomen who are not be candidates for standardised cancer treatment.Presented at the European Congress of Radiology, Vienna, September 15–20,1991     

Spinal deformity after intra-operative radiotherapy for paediatric patients

The purpose of this study was to clarify the incidence and characteristics of late-onset complications of the spine in children who underwent intra-operative radiation therapy (IORT) for common paediatric malignant tumours. 12 children with more than 4 years of follow-up after IORT were included and, in 11 of these, thoracic and/or lumbar spines were irradiated. To compare doses of irradiation to the spine with the resulting deformities, dose simulations of IORT were carried out on two selected cases using a radiation treatment planning system with a pencil-beam algorithm. The mean follow-up period was 135 months (range, 53–234 months). Radiographic reviews found spinal deformity in six patients. Only one patient was symptomatic and the spinal deformity was severe (Grade 3), whereas spinal deformity was mild in the remaining five patients without clinical symptoms (Grade 1). In all of the six patients, anterior wedge-shaped deformity was dominant, and scoliosis was found in only two patients. In one particular case with nephrectomy, irradiation had penetrated much deeper than usual at the site of nephrectomy, and dose distribution was asymmetric, causing clinically significant spinal deformity with scoliosis. In conclusion, specific deformities of the spine observed after IORT can be explained on the basis of dose distribution of the electron beam to the spine.Identification of late morbidity of paediatric cancer therapy has become increasingly important, as recent therapeutic developments have improved the survival rate of affected children. Radiation-induced bone injury is one of the hazardous problems: a high dose of radiation therapy impairs bone growth and gives rise to physical disabilities in affected children. Late complications following skeletal irradiation for childhood tumours have been reported previously [1–6].Intra-operative radiation therapy (IORT) is a technical refinement of radiation therapy that allows sparing of the dose-limiting tissues adjoining the target region. Following gross tumour removal, surgical displacement of critical organs or shielding of adjacent structures is carried out to minimise the radiation damage to the normal structure, and at the same time to deliver an effective irradiation dose to the therapeutic target in a single session. A high dose of electron beam irradiation with the proper acceleration energy can be delivered to residual tumours at the surgical site and neighbouring areas at high risk for microscopic disease. Combined with intensive chemotherapy, IORT has been applied successfully to paediatric malignant tumours [7–15]. In general, IORT has fewer and less severe adverse effects than conventional radiation therapy (external beam radiation therapy (EBRT)). However, the prevalence of arterial and ureteral stenosis following IORT has attracted particular attention recently [16]. The reason that IORT and EBRT are associated with different patterns of complications may result from differences in dose fractionation and distribution between electron beams and high-energy X-ray beams. Moreover, electron beams have a shorter range in bony tissue than X-ray beams and therefore present very different dose distribution patterns to X-rays. This suggests that the biological effects of IORT may be particularly unpredictable in the paraspinal region of patients. The purpose of this study was to clarify the incidence and characteristics of late-onset complications of the spine in children who underwent IORT for common paediatric malignant tumours (mostly for neuroblastoma). We focused on serial radiological changes and reviewed the medical records of long-term survivors retrospectively.     

Intraoperative Strahlentherapie (IORT) in der Behandlung des Mammakarzinoms - eine neue therapeutische Alternative im Rahmen der brusterhaltenden Therapie? Stellenwert und Zukunftsperspektiven. Erfahrungsbericht aus dem European Institute of Oncology (EIO), Mailand

Hintergrund: Die externe Strahlentherapie (EBRT) ist ein integraler Bestandteil der brusterhaltenden Behandlung des Mammakarzinoms. In zwei publizierten Studien konnte gezeigt werden, dass der externe Boost durch eine intraoperative Applikation einer Einzeldosis von 10-25 Gy direkt auf das Tumorbett ohne Einbuße der lokalen Kontrolle ersetzt werden kann. Patientinnen und Methode: Um die Anwendbarkeit höherer intraoperativer Strahlendosen zu untersuchen, wurde am European Institute of Oncology in Mailand eine Dosiseskalationsstudie initiiert. Mittels einer portablen Elektronenstrahlenquelle mit variablen Strahlenenergien wurden intraoperative Dosen zwischen 10 und 22 Gy appliziert. Von Juli bis Dezember 1999 wurden 65 Patientinnen mit einem Mammakarzinom mit maximalem Tumordurchmesser bis 2,5 cm NO-1 mit einem medianen Alter von 58 Jahren (33-80 Jahren) intraoperativ bestrahlt. Zehn Patientinnen wurden mit 10 Gy, acht mit 15 Gy, acht mit 17 Gy, sechs mit 19 Gy und 33 mit 21-22 Gy behandelt. Patientinnen, bei denen 10 bzw. 15 Gy verabreicht wurden, erhielten zusätzlich eine externe Bestrahlung von 44 bzw. 40 Gy. Bei allen übrigen war die IORT die alleinige strahlentherapeutische Behandlung. Ergebnisse: Es wurden keine akuten bzw. intermediären Nebenwirkungen nach 3-9 Monaten in Zusammenhang mit der intraoperativen Strahlentherapie (IORT) beobachtet. Schlussfolgerungen: Die exakte intraoperative Platzierung des Tubus unter Sichtkontrolle durch Chirurgen und Strahlentherapeuten ermöglicht ein Höchstmaß an Präzision bei der Strahlenapplikation. Durch Vermeidung einer Mitbestrahlung von Haut und Subkutangewebe wird das potentielle Risiko einer Fibrosierung verringert; somit dürfte ein besseres kosmetisches Ergebnis zu erwarten sein. IORT-Dosen bis zu 22 Gy (entsprechend einer Äquivalenzdosis von 60 Gy EBRT) können sicher appliziert werden. Obwohl durch die IORT die Operationsdauer um ca. 20 Minuten verlängert wird, resultiert für die Patientin durch eine deutliche Verkürzung der Gesamtbehandlungszeit eine Verbesserung der Lebensqualität. Langzeitnachbeobachtungen sind erforderlich, um die Sicherheit der IORT hinsichtlich einer suffizienten lokalen Tumorkontrolle beurteilen zu können. Als nächster Schritt ist die Durchführung einer randomisierten Studie zum Vergleich der IORT als alleiniger Strahlentherapie mit der EBRT geplant. Background: External beam radiation therapy (EBRT) represnet an integral component of breast-conserving treatment. In published series it has been demonstrated that the external boost can be replaced by intraoperative radiotherapy (IORT) where irradiation at a single dose from 10 up to 15 Gy was safely delivered directly to the tumor bed. Patients and Methods: At the European Institute of Oncology, Milan, we initiated a dose escalation study to investigate the feasibility of applying single doses of IORT from 10 Gy up to 22 Gy. A portable IORT equipment with different electron energies was used. From July to December 1999, a total of 65 patients with T1-2 (max. 2.5 cm) NO-1 breast cancer, median age 58 years (range 33-80 years) was treated. Ten patients received 10 Gy, eight patients were treated with an IORT of 15 Gy, eight received 17 Gy, six had 19 Gy, and 33 were treated with 21-22 Gy. Patients with 10 and 15 Gy received an additional EBRT of 44 and 40 Gy, respectively. In all other patients IORT was the sole radiation treatment. Results: No acute side effects or intermediate untoward effects after a follow-up from three to nine months related to IORT were observed. Conclusions: Since the applicator can be safely placed under the control of the surgeon and radiotherapist IORT has the potential of accurately treating the tumor bed. Skin and subcutaneous tissue are not irradiated thus decreasing the potential risk of fibrosis and eventually obtaining a better cosmesis. With IORT single doses of 22 Gy being equivalent to a 60 Gy EBRT can sefely be delivered. Even so the average time of operation was prolonged by around 20 minutes IORT application ultimately improves the quality of life of the patients in shortening overall treatment. Long-term follow-up is necessary to demonstrate whether large single doses of IORT might have the potential of sufficient local tumor control without major side effects. As a future perspective a randomized trial comparing EBRT with IORT as sole treatment will be performed.     

Short- and long-term histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT)

Purpose: The histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT) were investigated in order to establish the tolerance of liver tissue to IORT, thus providing a framework for clinical IORT treatment of patients with metastatic disease to the liver. Materials and methods: Following partial resection of the liver, IORT in doses of 10, 20, 25, or 30Gy was applied to the resection plane and a non-surgically manipulated part of the liver of 25 beagles. Results: There were no postoperative complications, and no morbidity or mortality during a maximal follow-up of 5 years. Dogs were killed at 3 months, and 1, 2, 3 and 5 years following IORT. Light microscopic examination revealed capsular thickening, severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1-2 years following IORT. At 3-5 years, however, only mild parenchymal changes were found that consisted of slight periportal fibrosis, an incidental portal-central fibrous septum and vascular changes with endothelial proliferation and focal arteriolar hyalinosis. Conclusions: This study demonstrated that following partial hepatic resection, IORT to the liver in the canine model can be applied safely, without short- or long-term treatment morbidity. Although doses up to 30Gy resulted in severe local tissue damage 1-2 years following IORT, these changes were largely reversible due to hepatic regeneration.     

Intraoperative radiation therapy in the management of early stage breast cancer

Adjuvant radiotherapy (RT) following breast conserving surgery (BCS) is associated with an improvement in local control and a reduction in breast cancer mortality. While traditionally delivered with whole breast irradiation (WBI), novel approaches have looked to reduce the duration, target volume, and toxicity of adjuvant RT. One such approach is intraoperative radiation therapy (IORT), which delivers radiation at the time of surgery with 80–90% of patients not requiring additional WBI. The current review presents IORT techniques and outcomes from modern series evaluating IORT as monotherapy or as a tumor bed boost. Based on two randomized trials (TARGIT-A and ELIOT) with recent updates, concern regarding higher rates of local recurrence with IORT exist, whether using electrons or low-energy techniques. In contrast, data is promising regarding IORT used as a boost, with ongoing studies evaluating its role prospectively. With respect to toxicity, the data suggest IORT is associated with comparable to slightly lower rates of toxicity though there may be a higher risk of seroma requiring aspiration and fat necrosis with IORT. Given current data and guidelines, WBI or other partial breast techniques should remain the standard of care in early stage breast cancer patients, while IORT should not be utilized outside of prospective clinical trials at this time.     

Short- and long-term histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT)

PURPOSE: The histopathological changes in the canine liver following single high-dose intraoperative radiation therapy (IORT) were investigated in order to establish the tolerance of liver tissue to IORT, thus providing a framework for clinical IORT treatment of patients with metastatic disease to the liver. MATERIALS AND METHODS: Following partial resection of the liver, IORT in doses of 10, 20, 25, or 30 Gy was applied to the resection plane and a non-surgically manipulated part of the liver of 25 beagles. RESULTS: There were no postoperative complications, and no morbidity or mortality during a maximal follow-up of 5 years. Dogs were killed at 3 months, and 1, 2, 3 and 5 years following IORT. Light microscopic examination revealed capsular thickening, severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1 2 years following IORT. At 3-5 years, however, only mild parenchymal changes were found that consisted of slight periportal fibrosis, an incidental portal-central fibrous septum and vascular changes with endothelial proliferation and focal arteriolar hyalinosis. CONCLUSIONS: This study demonstrated that following partial hepatic resection, IORT to the liver in the canine model can be applied safely, without short- or long-term treatment morbidity. Although doses up to 30Gy resulted in severe local tissue damage 1-2 years following IORT, these changes were largely reversible due to hepatic regeneration.     

The American Brachytherapy Society consensus statement on intraoperative radiation therapy

PurposeAlthough radiation therapy has traditionally been delivered with external beam or brachytherapy, intraoperative radiation therapy (IORT) represents an alternative that may shorten the course of therapy, reduce toxicities, and improve patient satisfaction while potentially lowering the cost of care. At this time, there are limited evidence-based guidelines to assist clinicians with patient selection for IORT. As such, the American Brachytherapy Society presents a consensus statement on the use of IORT.MethodsPhysicians and physicists with expertise in intraoperative radiation created a site-directed guideline for appropriate patient selection and utilization of IORT.ResultsSeveral IORT techniques exist including radionuclide-based high-dose-rate, low-dose-rate, electron, and low-energy electronic. In breast cancer, IORT as monotherapy should only be used on prospective studies. IORT can be considered in the treatment of sarcomas with close/positive margins or recurrent sarcomas. IORT can be considered in conjunction with external beam radiotherapy for retroperitoneal sarcomas. IORT can be considered for colorectal malignancies with concern for positive margins and in the setting of recurrent gynecologic cancers. For thoracic, head and neck, and central nervous system malignancies, utilization of IORT should be evaluated on a case-by-case basis.ConclusionsThe present guidelines provide clinicians with a summary of current data regarding IORT by treatment site and guidelines for the appropriate patient selection and safe utilization of the technique. High-dose-rate, low-dose-rate brachytherapy methods are appropriate when IORT is to be delivered as are electron and low-energy based on the clinical scenario.     

Full-Dose Intraoperative Radiotherapy with Electrons in Breast Cancer

PURPOSE: To investigate the feasibility of applying exclusive intraoperative radiation therapy (IORT) after conservative surgery in limited-stage breast carcinoma and to evaluate late effects and cosmetic results after this new conservative treatment. PATIENTS AND METHODS: From October 2000 to November 2002, 47 consecutive patients with unifocal breast carcinoma up to a diameter of 2 cm received conservative surgery followed by IORT with electrons as the sole adjuvant local therapy. Three different dose levels were used: 20 Gy (seven patients), 22 Gy (20 patients), and 24 Gy (20 patients). Patients were evaluated using RTOG/EORTC scale to assess the incidence of late complications. During follow-up, a radiologic assessment with mammography and sonography was periodically performed and any breast-imaging alterations were reported. RESULTS: After a follow-up ranging from 36 to 63 months (median, 48 months), 15 patients developed breast fibrosis (grade 2 in 14 patients, grade 3 in one patient), two patients presented with grade 3 skin changes, one patient developed a clinically relevant fat necrosis, and one patient showed breast edema and pain. Two patients developed contralateral breast cancer and one distant metastases; no local relapses occurred. Asymptomatic findings of fat necrosis were observed at mammography in twelve patients (25.5%), while an hypoechoic area was revealed by sonography in ten patients (21.5%). In four patients (8%), mammographic and sonographic findings suggested malignant lesions and required a rebiopsy to confirm the benign nature of the lesion. CONCLUSION: IORT in breast carcinoma is still an experimental treatment option for select patients with breast cancer and its application should be restricted to prospective trials. Although preliminary data on local control are encouraging, a longer follow-up is needed to confirm the efficacy of IORT in breast cancer and to exclude that severe late complications compromise the cosmetic results or modify the radiologic breast appearance during follow-up increasing the need for additional investigations.