Stereotactic body radiotherapy for primary and metastatic liver tumors - the Mayo Clinic experience.

INTRODUCTION: To better understand the efficacy of liver SBRT we reviewed our prospectively collected institutional SBRT database. METHODS: Between May 2008 and March 2013, 80 patients with 104 liver lesions received SBRT. The Kaplan-Meier method estimated local control (LC), overall survival (OS). Cox proportional hazards regression models identified factors associated with LC and OS. RESULTS: The median follow-up for living patients was 38.6 months. Patients had primary (n=17) or metastatic (n=63) tumors. The median tumor size was 2.7 cm (range, 0.6-14.0). The 1 and 4 year rates of LC were 89.4% and 88%, respectively. Colorectal (CRC) metastasis was associated with lower rates of LC (p=0.013). OS at 1 and 4 years was 78% and 25%, respectively. Patients with CRC metastases had higher rates of OS (p=0.03). The occurrence of severe acute and late toxicity was 3.8% and 6.3%, respectively. CONCLUSIONS: SBRT should be studied in prospective clinical trials compared with other liver-directed treatment modalities.

Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT).

PURPOSE: Gastrointestinal injury occurs rarely with agents that affect the vascular endothelial growth factor receptor and with abdominal stereotactic body radiation therapy (SBRT). We explored the incidence of serious bowel injury (SBI) in patients treated with SBRT with or without vascular endothelial growth factor inhibitor (VEGFI) therapy. METHODS AND MATERIALS: Seventy-six patients with 84 primary or metastatic intra-abdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Of the patients, 20 (26%) received VEGFI within 2 years after SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The incidence of SBI (Common Terminology Criteria for Adverse Events, version 4.0, grade 3-5 ulceration or perforation) after SBRT was obtained, and the relationship between SBI and VEGFI was examined. RESULTS: In the combined population, 7 patients (9%) had SBI at a median of 4.6 months (range, 3-17 months) from SBRT. All 7 had received VEGFI before SBI and within 13 months of completing SBRT, and 5 received VEGFI within 3 months of SBRT. The 6-month estimate of SBI in the 26 patients receiving VEGFI within 3 months of SBRT was 38%. No SBIs were noted in the 63 patients not receiving VEGFI. The log-rank test showed a significant correlation between SBI and VEGFI within 3 months of SBRT (P=.0006) but not between SBI and radiation therapy bowel dose (P=.20). CONCLUSIONS: The combination of SBRT and VEGFI results in a higher risk of SBI than would be expected with either treatment independently. Local therapies other than SBRT may be considered if a patient is likely to receive a VEGFI in the near future.

Intraoperative Electron Beam Radiotherapy (IOERT) in the management of locally advanced or recurrent cervical cancer.

BACKGROUND: To report outcomes in women with locally recurrent or advanced cervical cancer who received intraoperative electron beam radiotherapy (IOERT) as a component of therapy. METHODS: From 1983 to 2010, 86 patients with locally recurrent (n = 73, 85%) or primary advanced (n = 13, 15%) cervical cancer received IOERT following surgery. Common surgeries included pelvic exenteration (n = 26; 30%) or sidewall resection (n = 22; 26%). The median IOERT dose was 15 Gy (range, 6.25-25 Gy). Sixty-one patients (71%) received perioperative external beam radiotherapy (EBRT; median dose, 45 Gy). Forty-one patients (48%) received perioperative chemotherapy. RESULTS: Median follow-up was 2.7 years (range, 0.1-25.5 years). Resections were classified as R0 (n = 35, 41%), R1 (n = 30, 35%), or R2 (n = 21, 24%). Cumulative incidences of central (within the IOERT field) and locoregional relapse at 3 years were 23 and 38%, respectively. The 3-year cumulative incidence of distant relapse was 43%. Median survival was 15 months, and 3-year Kaplan-Meier estimates of cause-specific (CSS) and overall survival (OS) were 31 and 25%, respectively. On multivariate analysis, pelvic exenteration (p = 0.02) and perioperative EBRT (p = 0.009) were associated with improved central control in patients with recurrent disease. Recurrence within 6 months of initial therapy was associated with reduced CSS (p = 0.001). Common IOERT-related toxicities included peripheral neuropathy (n = 16), ureteral stenosis (n = 4), and bowel fistula/perforation (n = 4). Eleven of 16 patients with neuropathy required long-term pain medication. CONCLUSIONS: Long-term survival is possible with combined modality therapy including IOERT for advanced cervical cancer. Distant relapse is common, yet a significant number of patients experienced local progression in spite of aggressive treatment. In addition to consideration of disease- and treatment-related morbidity, other factors to be considered when selecting patients for this approach include the time interval from initial therapy to recurrence and whether the patient is able to receive perioperative EBRT and pelvic exenteration in addition to IOERT.

The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer.

OBJECTIVES: The optimal adjuvant therapy for International Federation of Gynecology and Obstetrics (FIGO) stage I papillary serous (UPSC) or clear cell (CC) endometrial cancer is unknown. We report on the largest single-institution experience using adjuvant high-dose-rate vaginal brachytherapy (VBT) for surgically staged women with FIGO stage I UPSC or CC endometrial cancer. METHODS AND MATERIALS: From 1998-2011, 103 women with FIGO 2009 stage I UPSC (n=74), CC (n=21), or mixed UPSC/CC (n=8) endometrial cancer underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant high-dose-rate VBT. Nearly all patients (n=98, 95%) also underwent extended lymph node dissection of pelvic and paraortic lymph nodes. All VBT was performed with a vaginal cylinder, treating to a dose of 2100 cGy in 3 fractions. Thirty-five patients (34%) also received adjuvant chemotherapy. RESULTS: At a median follow-up time of 36 months (range, 1-146 months), 2 patients had experienced vaginal recurrence, and the 5-year Kaplan Meier estimate of vaginal recurrence was 3%. The rates of isolated pelvic recurrence, locoregional recurrence (vaginal+pelvic), and extrapelvic recurrence (including intraabdominal) were similarly low, with 5-year Kaplan-Meier estimates of 4%, 7%, and 10%, respectively. The estimated 5-year overall survival was 84%. On univariate analysis, delivery of chemotherapy did not affect recurrence or survival. CONCLUSIONS: VBT is effective at preventing vaginal relapse in women with surgical stage I UPSC or CC endometrial cancer. In this cohort of patients who underwent comprehensive surgical staging, the risk of isolated pelvic or extrapelvic relapse was low, implying that more extensive adjuvant radiation therapy is likely unnecessary.

Stereotactic body radiotherapy in the treatment of adrenal metastases.

OBJECTIVES: To evaluate the dosimetry, clinical outcomes, and toxicity of patients treated with stereotactic body radiotherapy (SBRT) for adrenal metastases. MATERIALS AND METHODS: From February 2009 to February 2011, a total of 13 patients were treated with SBRT for metastases to the adrenal glands. Median age was 71 years (range, 60.8 to 83.2). Primary sites included lung (n=6), kidney (n=2), skin (n=2), bladder (n=1), colon (n=1), and liver (n=1). Nine patients had metastases to the left adrenal gland and 4 to the right. The median prescribed total dose was 45 Gy (range, 33.75 to 60 Gy), all in 5 fractions. RESULTS: Median follow-up for living patients was 12.3 months (range, 3.1 to 18 mo). Twelve of the 13 patients (92.3%) were evaluable for local control (LC). The crude LC rate was 100%, with no cases of local or marginal failure. Two patients had a complete response to treatment, 9 patients had a partial response, and 1 patient displayed stable disease. One-year overall survival and distant control were 62.9% and 55%, respectively. Median OS was 7.2 months (range, 2 to 18 mo). Grade 2 nausea was noted in 2 patients. CONCLUSIONS: SBRT seems to be a safe and effective measure to achieve LC for adrenal metastases.

Clinical outcomes and toxicity using stereotactic body radiotherapy (SBRT) for advanced cholangiocarcinoma.

BACKGROUND: To report single-institutional clinical outcomes and toxicity with SBRT for cholangiocarcinoma. METHODS: From March 2009 to July 2011, 10 patients with 12 unresectable primary (n = 6) or recurrent (n = 6) cholangiocarcinoma lesions underwent abdominal SBRT. Sites treated included liver (n = 10), abdominal lymph nodes (n = 1), and adrenal gland (n = 1). SBRT was delivered in three (n = 2) or five (n = 10) consecutive daily fractions over one week. The median prescription dose was 55 Gy (range, 45-60). Treatment response was graded by RECIST v.1.1, and toxicities were scored by CTCAE v.4.0. Data was analyzed using the Kaplan-Meier method to determine rates of local control (LC), freedom from distant progression (FFDM) and overall survival (OS). RESULTS: The median follow-up was 14 months (range, 2-26 months). LC, defined as freedom from progression within the SBRT field, was 100%, but four patients treated to intrahepatic sites experienced progression elsewhere in the liver. Estimates for FFDM at 6 and 12 months were 73% and 31%, respectively. Sites of disease relapse included liver (n = 3), liver and lymph nodes (n = 1), liver and lungs (n = 1), lymph nodes (n = 1), and mesentery (n = 1). OS estimates for the cohort at 6 and 12 months were 83% and 73%, respectively. The most common Grade ≥ 2 early toxicities were Grade 2 nausea and vomiting (n = 5) and gastrointestinal pain (n = 2). Late ≥ 2 toxicities included Grade 2 gastrointestinal pain (n = 3), Grade 3 biliary stenosis (n = 1), and Grade 5 liver failure (n = 1). CONCLUSIONS: SBRT shows promise as an effective local therapy for properly-selected patients with cholangiocarcinoma. Further follow-up is needed to better quantify the risk of late complications associated with SBRT.

Long-term outcomes with intraoperative radiotherapy as a component of treatment for locally advanced or recurrent uterine sarcoma.

PURPOSE: To report our institutional experience with intraoperative radiotherapy (IORT) as a component of treatment for women with locally advanced or recurrent uterine sarcoma. METHODS AND MATERIALS: From 1990 to 2010, 16 women with primary (n = 3) or locoregionally recurrent (n = 13) uterine sarcoma received IORT as a component of combined modality treatment. Tumor histology studies found leiomyosarcoma (n = 9), endometrial stromal sarcoma (n = 4), and carcinosarcoma (n = 3). Surgery consisted of gross total resection in 2 patients, subtotal resection in 6 patients, and resection with close surgical margins in 8 patients. The median IORT dose was 12.5 Gy (range, 10-20 Gy). All patients received perioperative external beam radiotherapy (EBRT; median dose, 50.4 Gy; range, 20-62.5 Gy), and 6 patients also received perioperative systemic therapy. RESULTS: Seven of the 16 patients are alive at a median follow-up of 44 months (range, 11-203 months). The 3-year Kaplan-Meier estimate of local relapse (within the EBRT field) was 7%, and central control (within the IORT field) was 100%. No local failures occurred in any of the 6 patients who underwent subtotal resection. The 3-year freedom from distant relapse was 48%, with failures occurring most frequently in the lungs or mediastinum. Median survival was 18 months, and 3-year Kaplan-Meier estimates of cause-specific and overall survival were 58% and 53%, respectively. Three patients (19%) experienced late Grade 3 toxicity. CONCLUSIONS: A combined modality approach with perioperative EBRT, surgery, and IORT for locally advanced or recurrent uterine sarcoma resulted in excellent local disease control with acceptable toxicity, even in patients with positive resection margins. With this approach, some patients were able to experience long-term freedom from recurrence.

Stereotactic body radiation therapy in the treatment of oligometastatic prostate cancer.

PURPOSE/OBJECTIVE(S): To report outcomes and toxicity for patients with oligometastatic (≤5 lesions) prostate cancer (PCa) treated with stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: Seventeen men with 21 PCa lesions were treated with SBRT between February 2009 and November 2011. All patients had a detectable prostate-specific antigen (PSA) at the time of SBRT, and 11 patients (65%) had hormone-refractory (HR) disease. Treatment sites included bone (n = 19), lymph nodes (n = 1), and liver (n = 1). For patients with bone lesions, the median dose was 20 Gy (range, 8-24 Gy) in a single fraction (range, 1-3). All but two patients received some form of anti-androgen therapy after completing SBRT. RESULTS: Local control (LC) was 100%, and the PSA nadir was undetectable in nine patients (53%). The first post-SBRT PSA was lower than pre-treatment levels in 15 patients (88%), and continued to decline or remain undetectable in 12 patients (71%) at a median follow-up of 6 months (range, 2-24 months). Median PSA measurements before SBRT and at last follow-up were 2.1 ng/dl (range, 0.13-36.4) and 0.17 ng/dl (range, <0.1-140), respectively. Six (55%) of the 11 patients with HR PCa achieved either undetectable or declining PSA at a median follow-up of 4.8 months (range, 2.2-6.0 months). Reported toxicities included one case each of grade 2 dyspnea and back pain, there were no cases of grade ≥3 toxicity following treatment. CONCLUSION: We report excellent LC with SBRT in oligometastatic PCa. More importantly, over half the patients achieved an undetectable PSA after SBRT. Further follow-up is necessary to assess the long-term impact of SBRT on LC, toxicity, PSA response, and clinical outcomes.

Clinical outcomes and dosimetric considerations using stereotactic body radiotherapy for abdominopelvic tumors.

PURPOSE/OBJECTIVES: To present clinical outcomes, early toxicity, and dosimetric constraints for patients undergoing stereotactic body radiation therapy (SBRT) for abdominal or pelvic tumors. MATERIALS AND METHODS: From May 2008 to February 2010, 47 patients with 50 lesions in proximity to hollow viscous organs at risk, including stomach, duodenum, small bowel, and colon, underwent SBRT at Mayo Clinic. Treated sites included liver (21), lymph node (14), adrenal gland (6), intramuscular (4), pancreas (3), and spleen (2). Treatment planning was performed with full body immobilization and 4-dimensional computed tomography (CT)-based planning with daily cone-beam CT or stereoscopic kV imaging for pretreatment image guidance. SBRT was delivered in 1 to 5 consecutive daily fractions in a single week. The most commonly prescribed dose was 50 Gy in 5 fractions (median 45 Gy, range: 20 to 60 Gy). Toxicities were scored by CTCAE v.3. Local failure was defined as per the Response Evaluation Criteria in Solid Tumors. RESULTS: Median follow-up was 12 months (range: 2 to 28 mo). Tumor responses of the 48 target lesions evaluable by Response Evaluation Criteria in Solid Tumor were complete response in 18 lesions (36%), partial response in 12 lesions (24%), stable disease in 12 lesions (24%), and progressive disease in 6 lesions (12%). Kaplan-Meier estimates of local control, overall survival, and freedom from metastasis at 6 and 12 months were 98%, 90%, and 63%, and 87%, 62%, 37%, respectively. Treatment was well-tolerated acutely without reported grade ≥3 toxicity. Five grade 3 late toxicities were reported, and 1 patient died of complications from duodenal perforation 11 months after SBRT. No dose correlation with toxicity could be established. CONCLUSIONS: SBRT is a practical treatment option for patients with abdominopelvic tumors. Relapse typically occurs outside treatment fields, and most patients achieve a favorable response. The dose constraints used in this cohort of patients was associated with acceptable early treatment-related toxicity.

Intraoperative electron beam radiotherapy (IOERT) in the management of recurrent ovarian malignancies.

OBJECTIVE: To investigate disease control, survival outcomes, and tolerance of intraoperative electron beam radiation therapy (IOERT) as a component of treatment for women with recurrent ovarian malignancies. METHODS: From November 1987 to January 2009, 20 patients with recurrent ovarian malignancies received IOERT after maximal surgical cytoreduction. Areas treated included the pelvis (14), para-aortic nodes (6), or inguinal nodes (1). The median IOERT dose was 12.5 Gy (range, 10-22.5 Gy). Sixteen patients also received perioperative external beam radiotherapy as a component of treatment (median, 50 Gy; range, 20-54.3 Gy). All patients were followed prospectively for outcome and toxicity evaluation. RESULTS: Median follow-up for surviving patients was 76.2 months (range, 1.5-175.8 months). The 5-year Kaplan-Meier estimate of local control was 59%, and central control (within the IOERT field) was 76%. All local relapses occurred in patients who had microscopic margin-positive resections. The 5-year freedom from distant relapse was 37%. The median disease-free interval after IOERT was 14 months. The median survival was 30 months, and the 5-year Kaplan-Meier estimate of survival was 49%. Six patients (29%) experienced grade 3 or higher toxicities, 2 of which (10%) were at least partly attributable to IOERT. Three patients experienced grade 1 or 2 peripheral neuropathy related to IOERT. CONCLUSIONS: Combined modality therapy with external beam radiotherapy, surgery, and IOERT is an option for the treatment of localized recurrent ovarian cancer, with acceptable rates of in-field failure and toxicity. Durable disease control is possible in select women treated with this regimen.

Image-guided radiotherapy (IGRT) for prostate cancer comparing kV imaging of fiducial markers with cone beam computed tomography (CBCT).

PURPOSE: To present our single-institution experience with image-guided radiotherapy comparing fiducial markers and cone-beam computed tomography (CBCT) for daily localization of prostate cancer. METHODS AND MATERIALS: From April 2007 to October 2008, 36 patients with prostate cancer received intensity-modulated radiotherapy with daily localization by use of implanted fiducials. Orthogonal kilovoltage (kV) portal imaging preceded all 1244 treatments. Cone-beam computed tomography images were also obtained before 286 treatments (23%). Shifts in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) dimensions were made from kV fiducial imaging. Cone-beam computed tomography shifts based on soft tissues were recorded. Shifts were compared by use of Bland-Altman limits of agreement. Mean and standard deviation of absolute differences were also compared. A difference of 5 mm or less was acceptable. Subsets including start date, body mass index, and prostate size were analyzed. RESULTS: Of 286 treatments, 81 (28%) resulted in a greater than 5.0-mm difference in one or more dimensions. Mean differences in the AP, SI, and LR dimensions were 3.4 ± 2.6 mm, 3.1 ± 2.7 mm, and 1.3 ± 1.6 mm, respectively. Most deviations occurred in the posterior (fiducials, 78%; CBCT, 59%), superior (79%, 61%), and left (57%, 63%) directions. Bland-Altman 95% confidence intervals were -4.0 to 9.3 mm for AP, -9.0 to 5.3 mm for SI, and -4.1 to 3.9 mm for LR. The percentages of shift agreements within ±5 mm were 72.4% for AP, 72.7% for SI, and 97.2% for LR. Correlation between imaging techniques was not altered by time, body mass index, or prostate size. CONCLUSIONS: Cone-beam computed tomography and kV fiducial imaging are similar; however, more than one-fourth of CBCT and kV shifts differed enough to affect target coverage. This was even more pronounced with smaller margins (3 mm). Fiducial imaging requires less daily physician input, is less time-consuming, and is our preferred method for prostate image-guided radiotherapy.

Overall and cause-specific survival for patients undergoing lobectomy, near-total, or total thyroidectomy for differentiated thyroid cancer.

BACKGROUND: The extent of surgery for well-differentiated thyroid cancer remains controversial. The purpose of this study was to evaluate the type of resection, age, T classification, nodal status, tumor size, and year of diagnosis for overall survival (OS) and cause-specific survival (CSS) using a large database. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 23,605 subjects were identified with papillary or follicular thyroid cancer between 1983 and 2002. OS and CSS were estimated, and outcomes for local excision, lobectomy, near-total thyroidectomy, or total thyroidectomy were compared. RESULTS: Ten-year OS and CSS by surgery were: total thyroidectomy, 90.4% and 96.8%, respectively; near-total thyroidectomy, 89.5% and 96.6%, respectively; and lobectomy, 90.8% and 98.6%, respectively. Controlling for risk factors, near-total thyroidectomy was inferior to total thyroidectomy for OS (hazard ratio [HR] 1.21; p = .019) and CSS (HR 1.39; p = .019). Age, T3/T4 disease, positive nodes, and tumor size were associated with poorer outcomes. CONCLUSION: Total thyroidectomy resulted in improved survival. Therapy should be individualized, accounting for potential complications and recurrence patterns.

An analysis of simulation for adjuvant intracavitary high-dose-rate brachytherapy in early-stage endometrial cancer.

PURPOSE: The utility of serial simulations in vaginal vault irradiation is controversial. Our primary endpoint was to assess the significance of simulation in women who received adjuvant intracavitary high-dose-rate brachytherapy (HDR-BT) for early-stage endometrial adenocarcinoma. Secondary endpoints included assessment of acute and late treatment toxicity, medication requirements, and charges related to the HDR-BT simulation and procedure. METHODS AND MATERIALS: Twenty-four consecutive women with early-stage endometrial cancer treated with adjuvant HDR-BT were evaluated. Descriptive statistical analyses were performed on the ratio of calculated to prescription BT dose at predefined dosimetric points. Data on acute and late toxicities, medication usage, and simulation charges were evaluated and compared. RESULTS: The intravaginal cylinder was placed three times over 10-14 days (median 6.5Gy prescribed to 5mm). No substantial deviation in the means of the calculated ratios was observed except at the bladder point (mean 0.77+/-0.23). Early toxicity was found to be no greater than Grade 1 (n=5). Serious late toxicities were uncommon; one woman developed a Grade 3 gastrointestinal toxicity. Half of the women required prescription medication incident to simulation. The average simulation charge was $1252.80. CONCLUSIONS: Despite the broad range of doses calculated at the bladder point, genitourinary toxicity was minimal. Simulation proved useful in recording dose and represented a small, yet important portion of the total treatment charge but did not alter treatment in this series. The necessity of simulation for intracavitary high-dose-rate vaginal brachytherapy remains unclear.

Effect of experimental genital mycoplasmosis on production of matrix metalloproteinases in membranes and amniotic fluid of Sprague-Dawley rats.

PROBLEM: Preterm, premature rupture of membranes (PPROM) is a dire pregnancy outcome that is frequently associated with infection by the genital mycoplasmas, Mycoplasma hominis, Ureaplasma parvum, and U. urealyticum. One potential mechanism by which these microorganisms may cause PPROM is by increasing the concentration of matrix metalloproteinases (MMPs) in the membranes and amniotic fluid. We tested this hypothesis in a well-defined model system of genital infection with M. pulmonis, a natural reproductive pathogen of rats. METHOD OF STUDY: Timed-pregnant, specific pathogen-free, Sprague-Dawley rats were infected with 10(7) CFU M. pulmonis at gestation day (gd) 14. Controls received an equivalent volume (100 microL) of sterile medium. At gd 18, rats were euthanized, and membranes and amniotic fluids were harvested and stored at -70 degrees C until analysis. Proteinase activity of amniotic fluid and membranes was resolved on discontinuous 7.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gelatin zymography gels. Band intensity was determined using a digital gel documentation system and the manufacturer's software (Kodak). RESULTS: Gelatinolytic activity associated with a band similar in molecular weight to ProMMP-9 (92 kDa, the inactive precursor of MMP-9) was significantly increased in amniotic fluids and membranes harvested from M. pulmonis-treated pups at gd 18 when compared with tissues harvested from control pups. Both ProMMP-9 and ProMMP-2 (72 kDa, the inactive precursor of MMP-2) were increased in infected animals at gd 21. CONCLUSION: Our study suggests that the genital mycoplasmas can increase MMP-9 production in vivo.