A clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma.
ABSTRACT: Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered.The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50-56?Gy) followed by surgery and IORT (10-12?Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population.The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity.NCT01566123.
Project description:Neoadjuvant therapy including chemotherapy alone or concurrent chemotherapy with external bream radiation is a standard treatment strategy for borderline resectable pancreatic adenocarcinoma and is also used routinely for primary operable cancers at some institutions (1). The use of intraoperative radiation therapy (IORT) has been limited largely because of the logistical issues in delivery of radiation during surgery (2). This is the first reported case of a borderline resectable pancreas cancer patient who underwent neoadjuvant chemo-radiation therapy followed by resection with the use of IORT using the mobile IntraBeam device to boost the resection bed and improve local control by dose escalation.
Project description:To compare the radiobiological response between simultaneously dose-escalated and non-escalated intensity-modulated radiation therapy (DE-IMRT and NE-IMRT) for patients with upper thoracic esophageal cancer (UTEC) using radiobiological evaluation.Computed tomography simulation data sets for 25 patients pathologically diagnosed with primary UTEC were used in this study. DE-IMRT plan with an escalated dose of 64.8 Gy/28 fractions to the gross tumor volume (GTV) and involved lymph nodes from 25 patients pathologically diagnosed with primary UTEC, was compared to an NE-IMRT plan of 50.4 Gy/28 fractions. Dose-volume metrics, tumor control probability (TCP), and normal tissue complication probability for the lung and spinal cord were compared. In addition, the risk of acute esophageal toxicity (AET) and late esophageal toxicity (LET) were also analyzed.Compared with NE-IMRT plan, we found the DE-IMRT plan resulted in a 14.6 Gy dose escalation to the GTV. The tumor control was predicted to increase by 31.8%, 39.1%, and 40.9% for three independent TCP models. The predicted incidence of radiation pneumonitis was similar (3.9% versus 3.6%), and the estimated risk of radiation-induced spinal cord injury was extremely low (<0.13%) in both groups. Regarding the esophageal toxicities, the estimated grade ≥2 and grade ≥3 AET predicted by the Kwint model were increased by 2.5% and 3.8%. Grade ≥2 AET predicted using the Wijsman model was increased by 14.9%. The predicted incidence of LET was low (<0.51%) in both groups.Radiobiological evaluation reveals that the DE-IMRT dosing strategy is feasible for patients with UTEC, with significant gains in tumor control and minor or clinically acceptable increases in radiation-induced toxicities.
Project description:Soft-tissue sarcoma (STS) represent a rare tumor entity, accounting for less than 1% of adult malignancies. The cornerstone of curative intent treatment is surgery with free margins, although the extent of the surgical approach has been subject to change in the last decades. Multimodal approaches usually including radiation therapy have replaced extensive surgical procedures in order to preserve functionality while maintaining adequate local control. However, the possibility to apply adequate radiation doses by external beam radiation therapy (EBRT) can be limited in some situation especially in case of directly adjacent organs at risk with low radiation tolerance. Application of at least a part of the total dose via intraoperative radiation therapy (IORT) with a single fraction during the surgical procedure may overcome those limitations, because radiosensitive structures can be moved out of the radiation field resulting in reduced toxicity while the enhanced biological effectivity of the high single dose improves local control. The current review summarizes rationale, techniques, oncological and functional outcomes including possible pitfalls and associated toxicities based on the published literature for IORT focusing on extremity and retroperitoneal STS. In extremity STS, combination of limb-sparing surgery, IORT and pre- or postoperative EBRT with moderate doses consistently achieved excellent local control rates at least comparable to approaches using EBRT alone but usually including patient cohorts with higher proportions of unfavourable prognostic factors. Further on, IORT containing approaches resulted in very high limb preservation rates and good functional outcome, probably related to the smaller high dose volume. In retroperitoneal STS, the combination of preoperative EBRT, surgery and IORT consistently achieved high local control rates which seem superior to surgery alone or surgery with EBRT at least with regard to local control and in some reports even to overall survival. Further on, preoperative EBRT in combination with IORT seems to be superior to the opposite combination with regard to local control and toxicity. No major differences in wound healing disturbances or postoperative complication rates can be observed with IORT compared to non-IORT containing approaches. Neuropathy of major nerves remains a dose limiting toxicity requiring dose restrictions or exclusion from target volume. Gastrointestinal structures and ureters should be excluded from the IORT area whenever possible and the IORT volume should be restricted to the available minimum. Nevertheless, IORT represents an ideal boosting method if combined with EBRT and properly executed by experiences users which should be further evaluated preferably in prospective randomized trials.
Project description:Radiation therapy (RT) is a curative treatment modality for localized prostate cancer. Over the past two decades, advances in technology and imaging have considerably changed RT in prostate cancer treatment. Treatment has evolved from 2-dimensional (2D) planning using X-ray fields based on pelvic bony landmarks to 3-dimensional (3D) conformal RT (CRT) which uses computed tomography (CT) based planning. Despite improvements with 3D-CRT, dose distributions often remained suboptimal with portions of the rectum and bladder receiving unacceptably high doses. In more recent years, intensity-modulated radiation therapy (IMRT) has become the standard of care to deliver external beam RT. IMRT uses multiple radiation beams of different shapes and intensities delivered from a wide range of angles to 'paint' the radiation dose onto the tumor. IMRT allows for a higher dose of radiation to be delivered to the prostate while reducing dose to surrounding organs. Multiple clinical trials have demonstrated improved cancer outcomes with dose escalation, but toxicities using 3D-CRT and escalated doses have been problematic. IMRT is a method to deliver dose escalated RT with more conformal dose distributions than 3D-CRT and has been associated with improved toxicity profiles. IMRT also appears to be the safest method to deliver hypofractionated RT and pelvic lymph node radiation. The purpose of this review is to summarize the technical aspects of IMRT planning and delivery, and to review the literature supporting the use of IMRT for prostate cancer.
Project description:BACKGROUND:Neoadjuvant external-beam radiotherapy (EBRT) with concomitant chemotherapy is the current standard-of-care for locally-advanced rectal cancer. Intraoperative radiotherapy (IORT) is to date only recommended for pelvic recurrences or incompletely resectable tumors. We here report on patients with stage II/III rectal cancer that were treated with IORT in a regional Russian university center due to limited access to EBRT. METHODS:We retrospectively analyzed data from patients that were diagnosed with locally-advanced rectal cancer and underwent surgery from December 2012 to October 2016 at a regional oncological center in Russia (Krasnodar). During this period, access to EBRT was limited due to a temporary lack of a sufficient number of EBRT facilities. Patients unable to travel to a distant radiotherapy site received IORT alone, those that could travel received neoadjuvant external beam (chemo-) radiotherapy. Factors of interest were tumor stage, tumor differentiation, resection status, surgery type and neoadjuvant or adjuvant chemotherapy. We assessed local progression-free survival (L-PFS), PFS and overall survival (OS). RESULTS:A total of 172 patients were included in this analysis. Of those, 92 (53.5%) were treated with IORT alone (median dose: 15?Gy [8.4-17?Gy]) and 80 (46.5%) received both neoadjuvant EBRT (median dose: 50.4?Gy [40-50.4?Gy]) and IORT (median dose: 15?Gy [15-17?Gy]). The median age was 65?years [33-82]. The median follow-up was 23?months [0-63?months]. The incidence of toxicity was low in both groups with an overall complication rate of 5.4%. Local PFS at 4?years was comparable with 59.4% in the IORT group and 65.4% in the IORT/EBRT group (p?=?0.70). Similarly, there was no difference in OS or PFS (p?=?0.66, p?=?0.51, respectively). CONCLUSIONS:IORT is a valuable option for patients with locally-advanced rectal cancer in the absence of access to EBRT.
Project description:Purpose:There are limited treatment options for locally advanced, unresectable pancreatic cancer (LAPC) and no likelihood of cure without surgery. Radiation offers an option for local control, but radiation dose has previously been limited by nearby bowel toxicity. Advances in on-board imaging and treatment planning may allow for dose escalation not previously feasible and improve local control. In preparation for development of clinical trials of dose escalation in LAPC, we undertook a dosimetric study to determine the maximum possible dose escalation while maintaining known normal tissue constraints. Methods and Materials:Twenty patients treated at our institution with either SBRT or dose-escalated hypofractionated IMRT (DE-IMRT) were re-planned using dose escalated SBRT to 70 Gy in 5 fractions to the GTV and 40 Gy in 5 fractions to the PTV. Standard accepted organ at risk (OAR) constraints were used for planning. Descriptive statistics were generated for homogeneity, conformality, OAR's and GTV/PTV. Results:Mean iGTV coverage by 50 Gy was 91% (±0.07%), by 60 Gy was 61.3% (±0.08%) and by 70 Gy was 24.4% (±0.05%). Maximum PTV coverage by 70 Gy was 33%. Maximum PTV coverage by 60 Gy was 77.5%. The following organ at risk (OAR) constraints were achieved for 90% of generated plans: Duodenum V20 < 30 cc, V30 < 3 cc, V35 < 1 cc; Small Bowel V20 < 15 cc, V30 < 1 cc, V35 < 0.1 cc; Stomach V20 < 20 cc, V30 < 2 cc, V35 < 1 cc. V40 < 0.5 cc was achieved for all OAR. Conclusions:Dose escalation to 60 Gy is dosimetrically feasible with adequate GTV coverage. The identified constraints for OAR's will be used in ongoing clinical trials.
Project description:Intraoperative radiotherapy (IORT) for early stage breast cancer is a technique for partial breast irradiation. There are several technologies in clinical use to perform breast IORT. Regardless of technique, IORT generally refers to the delivery of a single dose of radiation to the periphery of the tumor bed in the immediate intraoperative time frame, although some protocols have performed IORT as a second procedure. There are two large prospective randomized trials establishing the safety and efficacy of breast IORT in early stage breast cancer patients with sufficient follow-up time on thousands of women. The advantages of IORT for partial breast irradiation include: direct visualization of the target tissue ensuring treatment of the high-risk tissue and eliminating the risk of marginal miss; the use of a single dose coordinated with the necessary surgical excision thereby reducing omission of radiation and the selection of mastectomy for women without access to a radiotherapy facility or unable to undergo several weeks of daily radiation; favorable toxicity profiles; patient convenience and cost savings; radiobiological and tumor microenvironment conditions which lead to enhanced tumor control. The main disadvantage of IORT is the lack of final pathologic information on the tumor size, histology, margins, and nodal status. When unexpected findings on final pathology such as positive margins or positive sentinel nodes predict a higher risk of local or regional recurrence, additional whole breast radiation may be indicated, thereby reducing some of the convenience and low-toxicity advantages of sole IORT. However, IORT as a tumor bed boost has also been studied and appears to be safe with acceptable toxicity. IORT has potential efficacy advantages related to overall survival related to reduced cardiopulmonary radiation doses. It may also be very useful in specific situations, such as prior to oncoplastic reconstruction to improve accuracy of adjuvant radiation delivery, or when used as a boost in higher risk patients to improve tumor control. Ongoing international clinical trials are studying these uses and follow-up data are accumulating on completed studies.
Project description:Total mesorectal excision (TME) after neoadjuvant chemoradiotherapy (CRT) has offered superior control for patients with locally advanced rectal cancer, but can carry a quality of life cost. Fortunately, some patients achieve a complete response after CRT alone without the added morbidity caused by surgery. Efforts to increase fidelity of radiation treatment planning and delivery may allow for escalated doses of radiotherapy (RT) with limited off-target toxicity and elicit more pathological complete responses (pCR) to CRT thereby sparing more rectal cancer patients from surgery. In this review, methods of delivering escalated RT boost above 45-50.4 Gy are discussed including: 3D conformal, intensity-modulated radiotherapy (IMRT), and brachytherapy. Newly developed adaptive boost strategies and imaging modalities used in RT planning and response evaluation such as magnetic resonance imaging (MRI) and positron emission tomography (PET) are also discussed.
Project description:BACKGROUND:Advanced radiotherapy (RT) techniques allow normal tissue to be spared in patients with extremity soft tissue sarcoma (STS). This work aims to evaluate toxicity and outcome after neoadjuvant image-guided radiotherapy (IGRT) as helical intensity modulated radiotherapy (IMRT) with reduced margins based on MRI-based target definition in patients with STS. METHODS:Between 2010 to 2014, 41 patients with extremity STS were treated with IGRT delivered as helical IMRT on a tomotherapy machine. The tumor site was in the upper extremity in 6 patients (15%) and lower extremity in 35 patients (85%). Reduced margins of 2.5?cm in longitudinal direction and 1.0?cm in axial direction were used to expand the MRI-defined gross tumor volume, including peritumoral edema, to the clinical target volume. An additional margin of 5?mm was added to receive the planning target volume. The full total dose of 50?Gy in 2?Gy fractions was sucessfully applied in 40 patients. Two patients received chemotherapy instead of surgery due to systemic progression. All patients were included into a strict follow-up program and were seen interdisciplinarily by the Departments of Orthopaedic Surgery and Radiation Oncology. RESULTS:Thirty eight patients that received total RT total dose and subsequent resection were analyzed for outcome. After a median follow-up of 38.5?months cumulative OS, local PFS and systemic PFS at 2?years were determined at 78.2, 85.2 and 54.5%, respectively. Two of 6 local recurrences were proximal marginal misses. Negative resection margins were achieved in 84% of patients. The rate of major wound complications was comparable to previous IMRT studies with 36.8%. RT was overall tolerable with low toxicity rates. CONCLUSIONS:IMRT-IGRT offers neoadjuvant treatment for extremity STS with reduced safety margins and thus low toxicity rates. Wound complication rates were comparable to previously reported frequencies. Two reported marginal misses suggest a word of caution for reduction of longitudinal safety margins.
Project description:Locally recurrent rectal cancer may cause significant morbidity. Prior reports of rectal cancer reirradiation following local recurrence suggest treatment efficacy, with variable rates of late toxicity. Modern techniques including intensity modulated radiation therapy (IMRT) may improve the therapeutic index. We report outcomes for pelvic reirradiation as treatment for rectal cancer using IMRT.The records of 31 patients undergoing reirradiation for rectal cancer between 2004 and 2013 were reviewed. All patients underwent IMRT using an accelerated hyperfractionation (39 Gy in 1.5-Gy fractions delivered twice daily, n=15) or once-daily fractionation technique (median dose, 30.4 Gy; range, 27-40 Gy in 15-22 fractions; n = 16). The median cumulative dose was 77 Gy (range, 59-113), and the median interval from prior pelvic radiation therapy was 39.8 months (range, 10.1-307.6). Treatment intent was palliative in 20 patients and neoadjuvant or adjuvant in 11 patients. Surgery was generally reserved for patients with an isolated local recurrence. Concurrent chemotherapy was administered for 25/31 patients, most frequently capecitabine (n=11) or continuous infusion 5-fluorouracil (n=10).Median follow-up was 11.3 months. The prescribed treatment was completed in 29/31 patients (93.5%). Among 18 patients with symptoms attributable to recurrent disease, successful palliation was achieved in 10/18 (55.6%). The rate of grade 2 and grade 3 acute toxicities was 32.3% and 3.2%, respectively. Local control rates at 1 and 2 years were 61.3% and 47.3%, respectively. Median overall survival was 21.9 months, and 1-year survival was 66.7% for patients who had surgical resection versus 58.7% for those who did not (P = .0802).Rectal cancer reirradiation using IMRT is well-tolerated in the setting of prior pelvic radiation therapy. Given significant risk of local progression, further dose escalation may be warranted for patients with life expectancy exceeding 1 year.