Excellent local control with IOERT and postoperative EBRT in high grade extremity sarcoma: results from a subgroup analysis of a prospective trial.
ABSTRACT: To report the results of a subgroup analysis of a prospective phase II trial focussing on radiation therapy and outcome in patients with extremity soft tissue sarcomas (STS).Between 2005 and 2010, 50 patients (pts) with high risk STS (size ≥ 5 cm, deep/extracompartimental location, grade II-III (FNCLCC)) were enrolled. The protocol comprised 4 cycles of neoadjuvant chemotherapy with EIA (etoposide, ifosfamide and doxorubicin), definitive surgery with IOERT, postoperative EBRT and 4 adjuvant cycles of EIA. 34 pts, who suffered from extremity tumors and received radiation therapy after limb-sparing surgery, formed the basis of this subgroup analysis.Median follow-up from inclusion was 48 months in survivors. Margin status was R0 in 30 pts (88%) and R1 in 4 pts (12%). IOERT was performed as planned in 31 pts (91%) with a median dose of 15 Gy, a median electron energy of 6 MeV and a median cone size of 9 cm. All patients received postoperative EBRT with a median dose of 46 Gy after IOERT or 60 Gy without IOERT. Median time from surgery to EBRT and median EBRT duration was 36 days, respectively. One patient developed a local recurrence while 11 patients showed nodal or distant failures. The estimated 5-year rates of local control, distant control and overall survival were 97%, 66% and 79%, respectively. Postoperative wound complications were found in 7 pts (20%), resulting in delayed EBRT (>60 day interval) in 3 pts. Acute radiation toxicity mainly consisted of radiation dermatitis (grade II: 24%, no grade III reactions). 4 pts developed grade I/II radiation recall dermatitis during adjuvant chemotherapy, which resolved during the following cycles. Severe late toxicity was observed in 6 pts (18%). Long-term limb preservation was achieved in 32 pts (94%) with good functional outcome in 81%.Multimodal therapy including IOERT and postoperative EBRT resulted in excellent local control and good overall survival in patients with high risk STS of the extremities with acceptable acute and late radiation side effects. Limb preservation with good functional outcome was achieved in the majority of patients.ClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72, 17.06.2011.
Project description:To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123).Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31).Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy).We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3- and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3- and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years.Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up.NCT01566123.
Project description:High-grade soft-tissue sarcoma (STS) has a poor prognosis. The goal of this study was to review treatment outcomes of patients with high-grade STS treated with interdigitated neoadjuvant chemotherapy (CT) and radiation at our institution.Patients with high-grade STS (1997 to 2010) were planned for treatment with 3 cycles of neoadjuvant CT, interdigitated preoperative radiation therapy (44 Gy administered in split courses with a potential 16 Gy postoperative boost), and 3 cycles of postoperative CT. Cancer control outcomes at 3 years were analyzed.Sixteen patients with high-grade STS were evaluated. Median age was 53 years, the median longest tumor diameter was 14.6 cm, and median follow-up was 33 months. All 16 patients received 2 or 3 cycles of neoadjuvant CT and all patients completed neoadjuvant RT. The estimated 3-year rate for local control was 100%, disease-free survival 62.5%, and overall survival 73.4%.Patients with high-grade STS treated with interdigitated neoadjuvant CT and radiation before surgical resection had excellent rates of local control, along with disease-free survival and overall survival similar to previously published reports. This combined-modality approach continues to have a role in the treatment of patients with high-grade STS.
Project description:Purpose:This study aimed to assess the impact of radiation dose on rectal toxicity after salvage external beam radiation therapy (EBRT) with or without a brachytherapy boost for exclusive local failures after the primary EBRT for prostate cancer. Methods and materials:Fourteen patients with no severe residual late toxicity after primary EBRT?±?brachytherapy were reirradiated after a median time interval of 6.1 years. The median normalized total dose in 2?Gy fractions (NTD2Gy, ?/? ratio?=?1.5?Gy for prostate cancer cells) was 74?Gy at primary EBRT and 85.1?Gy at reirradiation. Rectal dose-volume histograms (converted to NTD2Gy_alpha/beta = 3?Gy) and the corresponding normal-tissue complication probability (NTCP) values for gastrointestinal (GI) toxicity were evaluated for 2 groups: High GI toxicity (grade ?3) and low GI toxicity (grade ?2). Results:The 5-year grade ?3 GI toxicity-free survival rate was 57.1%. The median rectal V70Gy and maximum dose to 1?cm3 (D1ccrect) at primary EBRT were both predictive for grade ?3 GI toxicity (9% vs 0%; P?=?.04 and 72.2?Gy vs 66.8?Gy; P?<?.01, respectively). When adding primary radiation therapy (RT) and reirradiation plans, the median D1ccrect was 139.8?Gy versus 126.7?Gy (P?<?.01) for high and low GI toxicity groups. NTCP >10% at primary RT was predictive for high GI toxicity at reirradiation (P?<?.05). Conclusions:Even in the absence of residual toxicity after primary RT, rectal doses >70?Gy and NTCP >10% calculated for a first irradiation may be associated with a higher risk of developing high GI toxicity at reirradiation with a possible D1ccrect threshold of 130?Gy.
Project description:We sought to reduce local recurrence for retroperitoneal sarcomas by using a coordinated strategy of advanced radiation techniques and aggressive en-bloc surgical resection.Proton-beam radiation therapy (PBRT) and/or intensity-modulated radiation therapy (IMRT) were delivered to improve tumor target coverage and spare selected adjacent organs. Surgical resection of tumor and adjacent organs was performed to obtain a disease-free anterior margin. Intraoperative electron radiation therapy (IOERT) was delivered to any close posterior margin.Twenty patients had primary tumors and eight had recurrent tumors. Tumors were large (median size 9.75 cm), primarily liposarcomas and leiomyosarcomas (71%), and were mostly of intermediate or high grade (81%). PBRT and/or IMRT were delivered to all patients, preferably preoperatively (75%), to a median dose of 50 Gy. Surgical resection included up to five adjacent organs, most commonly the colon (n = 7) and kidney (n = 7). Margins were positive for disease, usually posteriorly, in 15 patients (54%). IOERT was delivered to the posterior margin in 12 patients (43%) to a median dose of 11 Gy. Surgical complications occurred in eight patients (28.6%), and radiation-related complications occurred in four patients (14%). After a median follow-up of 33 months, only two patients (10%) with primary disease experienced local recurrence, while three patients (37.5%) with recurrent disease experienced local recurrence.Aggressive resection of retroperitoneal sarcomas can achieve a disease-negative anterior margin. PBRT and/or IMRT with IOERT may possibly deliver sufficient radiation dose to the posterior margin to control microscopic residual disease. This strategy may minimize radiation-related morbidity and reduce local recurrence, especially in patients with primary disease.
Project description:Introduction: Breast conserving surgery (BCS) followed by postoperative whole breast irradiation (WBI) is the current standard of care for early stage breast cancer patients. Boost to the tumor bed is recommended for patients with a higher risk of local recurrence and may be applied with different techniques. Intraoperative electron radiotherapy (IOERT) offers several advantages compared to other techniques, like direct visualization of the tumor bed, better skin sparing, less inter- and intrafractional motion, but also radiobiological effects may be beneficial. Objective of this retrospective analysis of IOERT as boost in breast cancer patients was to assess acute toxicity and early oncological outcomes. Material and Methods: All patients, who have been irradiated between 11/2014 and 01/2018 with IOERT during BCS were analyzed. IOERT was applied using the mobile linear accelerator Mobetron with a total dose of 10 Gy, prescribed to the 90% isodose. After ensured woundhealing, WBI followed with normofractionated or hypofractionated regimens. Patient reports, including diagnostic examinations and toxicity were analyzed after surgery and 6-8 weeks after WBI. Overall survival, distant progression-free survival, in-breast and contralateral breast local progression-free survival were calculated using the Kaplan-Meier method. Furthermore, recurrence patterns were assessed. Results: In total, 157 patients with a median age of 57 years were evaluated. Postoperative adverse events were mild with seroma and hematoma grade 1-2 in 26% and grade 3 in 0.6% of the patients. Wound infections grade 2-3 occurred in 2.2% and wound dehiscence grade 1-2 in 1.9% of the patients. Six to eight weeks after WBI radiotherapy-dependent acute dermatitis grade 1-2 was most common in 90.9% of the patients. Only 4.6% of the patients suffered from dermatitis grade 3. No grade 4 toxicities were documented after surgery or WBI. 2- and 3-year overall survival and distant progression-free survival, were 97.5 and 93.6, and 0.7 and 2.8%, respectively. In-breast recurrence and contralateral breast cancer rates after 3 years were 1.9 and 2.8%, respectively. Conclusion: IOERT boost during BCS is a safe treatment option with low acute toxicity. Short-term recurrence rates are comparable to previously published data and emphasize, that IOERT as boost is an effective treatment.
Project description:BACKGROUND:Locally recurrent rectal cancer (LRRC) after surgery or external beam radiotherapy (EBRT) is a serious challenge for which no standard treatment is defined. In the present study, we investigated the feasibility of computed tomography (CT)-guided radioactive 125I seed (RIS) implantation assisted with three-dimensional printing non-coplanar template (3D-PNCT) in LRRC patients who previously received surgery or EBRT. METHODS:Sixty-six patients with LRRC treated by CT-guided RIS implantation in our institute from December 2015 to May 2019 were included. The treatment procedure included: preoperative CT localization, planning design, the printing of 3D individualized template, CT-guided RIS implantation assisted with 3D-PNCT, and postoperative dose evaluation. Therapeutic outcomes including local control (LC) and overall survival (OS) were retrospectively evaluated, as well as side effects. RESULTS:All the patients had previously received surgery or EBRT. The median follow-up time was 12.2 (range, 2.5-35.9) months. The median radioactive activity of a single RIS was 0.6 (range, 0.43-0.72) mCi. The median number of RIS was 60, ranging from 10 to 175. The dosimetric parameters included D90 (140.7?±?33.1) Gy, D100 (90.3?±?138.6) Gy, and V100 (91.0?±?13.3) %. Pain relief was achieved in 85.1% (40/47) of patients. Besides, 9.1% (6/66) of patients had severe side effects (?grade 3), including perianal skin ulcer in 1 case, fistula, radiation proctitis, and intestinal obstruction each in two cases. Median OS time was 14.7 (95% confidence interval (CI): 13.0-16.3) months, and median LC time was 12.2 (95% CI: 9.1-15.2) months. Univariate analysis revealed that when D90?>?130?Gy or D100?>?55?Gy or V100?>?90%, the LC time was remarkably prolonged. However, none of the parameters significantly affected OS. CONCLUSIONS:CT-guided RIS implantation assisted with 3D-PNCT is an effective and safe salvage treatment strategy for patients with LRRC after EBRT or surgery. D90, D100, and V100 can be used as prognostic predictors. TRIAL REGISTRATION:NCT03890926 .
Project description:BACKGROUND:This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS:Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS:Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m(2). At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS:The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging.
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:Introduction:Pancreatic adenocarcinoma is an aggressive malignancy that has consistently demonstrated poor outcomes despite aggressive treatments. Despite multimodal treatment, local disease progression and local recurrence are common. Management of recurrent or progressive pancreatic carcinomas proves a further challenge. In patients previously treated with radiation therapy, stereotactic body radiation therapy (SBRT) is a promising modality capable of delivering high dose to the tumor while limiting dose to critical structures. We aimed to determine the feasibility and tolerability of SBRT for recurrent or local pancreatic cancer in patients previously treated with external beam radiation therapy (EBRT). Materials and methods:Patients treated with EBRT who developed recurrent or local pancreatic ductal adenocarcinoma treated with SBRT reirradiation at our institution, from 2004 to 2014 were reviewed. Our primary endpoints included overall survival (OS), local control, regional control, and late grade 3+ radiation toxicity. Endpoints were analyzed with the Kaplan-Meier method. The association of these survival endpoints with risk factors was studied with univariate Cox proportional hazards models. Results:We identified 38 patients with recurrent/progressive pancreatic cancer treated with SBRT following prior radiation therapy. Prior radiation was delivered to a median dose of 50.4?Gy in 28 fractions. SBRT was delivered to a median dose of 24.5?Gy in 1-3 fractions. Surgical resection was performed on 55.3% of all patients. Within a median follow-up of 24.4?months (inter-quartile range, 14.9-32.7?months), the median OS from diagnosis for the entire cohort was 26.6?months (95% CI: 20.3-29.8) with 2-year OS of 53.0%. Median survival from SBRT was 9.7?months (95% CI, 5.5-13.8). The 2-year freedom from local progression and regional progression was 58 and 82%, respectively. For the entire cohort, 18.4 and 10.5% experienced late grade 2+ and grade 3+ toxicity, respectively. Conclusion:This single institution retrospective review identified SBRT reirradiation to be a feasible and tolerable treatment strategy for patients with previous locally progressive or recurrent pancreatic adenocarcinoma.
Project description:Purpose/Objective: High-grade glioma is the most common primary malignant tumor of the CNS, with death often resulting from uncontrollable intracranial disease. Radiation dose may be limited by the tolerance of critical structures, such as the brainstem and optic apparatus. In this report, long-term outcomes in patients treated with conventionally fractionated stereotactic boost for tumors in close proximity to critical structures are presented. Materials/Methods: Patients eligible for inclusion in this single institution retrospective review had a pathologically confirmed high-grade glioma status post-surgical resection. Inclusion criteria required tumor location within one centimeter of a critical structure, including the optic chiasm, optic nerve, and brainstem. Radiation therapy consisted of external beam radiation followed by a conventionally fractionated stereotactic boost. Oncologic outcomes and toxicity were assessed. Results: Thirty patients eligible for study inclusion underwent resection of a high-grade glioma. The median initial adjuvant EBRT dose was 50 Gy with a median conventionally fractionated stereotactic boost of 10 Gy. All stereotactic treatments were given in 2 Gy daily fractions. Median follow-up time for the entire cohort was 38 months with a median overall survival of 45 months and 5-year overall survival of 32.5%. The median freedom from local progression was 45 months, and the 5-year freedom from local progression was 29.7%. Two cases of radiation retinopathy were identified following treatment. No patient experienced toxicity attributable to the optic chiasm, optic nerve, or brainstem and no grade 3+ radionecrosis was observed. Conclusions: Oncologic and toxicity outcomes in high-grade glioma patients with tumors in unfavorable locations treated with conventionally fractionated stereotactic boost are comparable to those reported in the literature. This treatment strategy is appropriate for those patients with resected high-grade glioma in close proximity to critical structures.