Evaluating outcomes and toxicities for a newly implemented MRI-based brachytherapy program for cervical cancer.

OBJECTIVE: We report an updated analysis of the outcomes and toxicities of MRI-based brachytherapy for locally advanced cervical cancer from a U.S. academic center. METHODS: A retrospective review was performed on patients treated with MRI-based brachytherapy for cervical cancer. EBRT was standardly 45 Gy in 25 fractions with weekly cisplatin. MRI was performed with the brachytherapy applicator in situ. Dose specification was most commonly 7 Gy for 4 fractions with optimization aim of D90 HR-CTV EQD2 of 85-95 Gyα/ß=10 Gy in 2 implants each delivering 2 fractions. RESULTS: Ninety-eight patients were included with median follow up of 24.5 months (IQR 11.9-39.8). Stage IIIA-IVB accounted for 31.6% of cases. Dosimetry results include median GTV D98 of 101.0 Gy (IQR 93.3-118.8) and HR-CTV D90 of 89 Gy (IQR 86.1-90.6). Median D2cc bladder, rectum, sigmoid, and bowel doses were 82.1 Gy (IQR 75.9-88.0), 65.9 Gy (IQR 59.6-71.2), 65.1 Gy (IQR 57.7-69.6), and 55 Gy (IQR 48.9-60.9). Chronic grade 3+ toxicities were seen in the bladder (8.2%), rectosigmoid (4.1%), and vagina (1.0%). Three-year LC, PFS, and OS were estimated to be 84%, 61.7%, and 76.1%, respectively. CONCLUSION: MRI-based brachytherapy demonstrates excellent local control and acceptable rates of high-grade morbidity. These results are possible in our population with relatively large volume primary tumors and extensive local disease.

Long-term Benefit of Tumor Volume-Directed Involved Field Radiation Therapy in the Management of Recurrent Ovarian Cancer.

OBJECTIVES: This study aimed to report on long-term effectiveness of involved field radiation therapy (IFRT) in the salvage of localized recurrent ovarian cancer (ROC). METHODS: A retrospective analysis of 27 patients with a diagnosis of epithelial ovarian cancer who received tumor volume-directed IFRT for localized extraperitoneal recurrences (either as consolidation after cytoreductive surgery (CRS) or as attempted salvage if unresectable) forms the basis of this report. All patients were heavily pretreated with multiple chemotherapy regimens. Involved field radiation therapy was primarily with external beam (median dose, 50.4 Gy). Local recurrence-free survival (LRFS) was defined as freedom from in-field recurrences and was considered as a measure of effectiveness of radiotherapy. Statistical analyses evaluated association between disease-free survival, overall survival, LRFS, and various prognostic factors. Comparison was also made with a similar but unmatched cohort with localized recurrences salvaged by additional chemotherapy instead of local therapies (NIFRT group). RESULTS: Of 27 patients, 17 had optimal CRS before RT. The actuarial survival at 5 and 10 years (in parenthesis) from date of radiation were LRFS (70% and 60%), overall survival (30% and 19%), and disease-free survival (33% and 20%). None of the NIFRT patients survived beyond 5 years from initiation of salvage chemotherapy. CONCLUSIONS: Long-term follow-up in this selected series confirmed the benefit of IFRT (±CRS) in localized ROC. Chemotherapy salvage in a similar NIFRT group was not equivalent, suggesting a role for locoregional therapies in selected patients with ROC.

Fatal case of luteinized thecoma with sclerosing peritonitis in a 40-year-old woman.

We describe the pathologic and clinical presentation of a very rare, fatal case of luteinized thecoma with sclerosing peritonitis in a 40-year-old woman, who had a history of total abdominal hysterectomy and a left salpingo-oophorectomy in 2003. The patient presented with abdominal pain, and radiologic examinations revealed a 10-cm heterogenous right pelvic mass with partial necrosis. The patient eventually underwent an exploratory laparotomy, which revealed an ovarian tumor with multiple implants in the peritoneal cavity. The ovarian lesion was made up of spindle cells among clusters of luteinized stromal cells that expanded to the ovarian cortex. Tumor cells were positive for vimentin, estrogen and progesterone receptors, and CCD68 (focally) and negative for CD34, α-smooth muscle actin, ß-catenin, and desmin by immunohistochemical studies. Luteinized cells were positive for α-inhibin and calretinin. Tumor cells exhibited low Ki-67 proliferation indices. The patient died because of the sclerosing peritonitis component of the disease.

Initial Experience with the Radiotracer 18F-Fluciclovine PET/CT in Ovarian Cancer.

OBJECTIVE: Early and accurate staging of ovarian cancer is paramount to disease survival. Conventional imaging including FDG PET/CT are limited in the evaluation of small metastatic lesions. 18F-Fluciclovine has minimal urine and bowel excretion allowing optimal visualization of the abdomen and pelvis. This study examines 18F-fluciclovine uptake in known primary and recurrent ovarian cancer. METHODS: Seven patients with a confirmed diagnosis of epithelial ovarian cancer underwent 18F-fluciclovine PET/CT imaging. Forty-one (41) lesions were identified with 18F-fluciclovine and confirmed to be true positive (n = 41). We aim to explore if 18F-fluciclovine uptake in ovarian lesions were greater than background uptake of bone marrow, blood pool, and bladder. Quantification analysis was performed to determine max and mean standard uptake values (SUVmax and SUVmean) of known and suspected lesions compared to SUVmean uptake of background structures. RESULTS: 18F-Fluciclovine demonstrated 100% sensitivity (41/41) for uptake in known ovarian lesions. The average SUVmax (±SD) uptake of known ovarian lesions was 5.9 (±2.6) and 5.1 (±2.0) on early and delayed images, respectively. The average tumor SUVmax to SUVmean of background (±SD) (T:B) ratios on early and delay were 1.9 (±0.8), 2.1 (±0.9) for marrow; 3.8 (±1.8), 3.4 (±1.5) for aorta; and 8.4 (±4.3), 1.5 (±1.7) for bladder, respectively. CONCLUSION: 18F-Fluciclovine uptake in malignant ovarian lesions was above background levels suggesting its feasibility in the imaging of ovarian cancer. Due to increasing tracer washout via the urinary bladder over time, early imaging at 4 min post injection is favorable.

A multi-institutional cohort study of adjuvant therapy in stage I-II uterine carcinosarcoma.

OBJECTIVE: To evaluate the impact of adjuvant post-operative therapy in women with early stage uterine carcinosarcoma. METHODS: After IRB approval was obtained at all sites, a multi-center retrospective study of women with FIGO stage I-II uterine carcinosarcoma diagnosed from 1997 to 2007 was conducted. Post-operative treatment included observation (OBS), radiation (RT), chemotherapy (CT) alone or with RT (CT+RT). Data analyzed included demographic and pathologic factors, adjuvant therapy outcomes, and time-to-event information. The Kaplan-Meier method was used to estimate time-to-event functions. Cox regression modeling was used to examine the impact of selected covariates on progression free survival (PFS), and overall survival (OS). RESULTS: 111 women were identified: 94 (85%) had stage I and 17 (15%) had stage II uterine carcinosarcoma. Forty-four women (40%) did not receive adjuvant therapy (OBS), 29 (26%) women had adjuvant CT, 23 (20%) women underwent RT and 15 (14%) women underwent RT+CT. Seventy-three patients were alive without disease and 38 had progressed or died at the close of data collection. In multivariate analysis, CT (p=0.003), LVSI (p<0.0001) and a pre-existing cancer (p=0.004) were most predictive of PFS. LVSI was predictive of shortened OS (p=0.01). CONCLUSIONS: In women with FIGO stage I-II uterine carcinosarcoma, adjuvant chemotherapy is associated with improved PFS compared to radiation or observation alone. Ongoing clinical trials will clarify the role of chemotherapy in women with this disease.

Hormone replacement after breast cancer: is it safe?

The use of hormone therapy for climacteric symptoms in patients with breast cancer has become a significant and important point of discussion due in part to the improved survival from this disease in recent years. There is a theoretic risk that exogenous hormones will stimulate the growth of microscopic disease and lead to decreased survival and increased recurrence. In addition, 2 large studies have shown that there is an association between hormone therapy and breast cancer risk in women without an earlier history of breast cancer. Other studies suggest that estrogen alone may have a superior safety profile than estrogen and progesterone in combination. Hormone therapy could be justified for improvement of quality of life when other options have failed and the patient is informed of the risks.

Uterine perforation during brachytherapy for cervical cancer: Complications, outcomes, and best practices for forward treatment planning and management.

PURPOSE: The purpose of the study was to determine the incidence of uterine perforations, review the associated complications, and propose guidelines for management of perforations after brachytherapy. METHODS AND MATERIALS: A retrospective chart review was conducted for all patients with cervical cancer who received single or multiple high-dose-rate brachytherapy implants between April 2006 and May 2017 at a single academic institution. CT and MRI images were retrospectively evaluated to record incidences of uterine perforation of tandem during brachytherapy. Acute and long-term complications during and after treatment were scored using the Common Terminology Criteria for Adverse Events, Version 4.0, of the National Cancer Institute. RESULTS: A total of 123 patients were included in the study. Perforations were observed in 22 patients (17.9%) with 31 (6.4%) of the 482 total implants. Of the different categories of adverse events, only the rate of acute infectious complications among those with perforations (n = 3, 13.6%) versus those without perforations (n = 3, 3.0%) was significant (p = 0.040). Two of the three perforated patients with acute infections had mild urinary tract infections, and all resolved without complications or treatment delays. The remaining one patient had a frank perforation of the anterior uterine wall with a subsequent Grade 3 pyometra infection despite administration of prophylactic antibiotics and 1-week treatment delay. This case was eventually resolved with cervical dilation and evacuation of fluid. Long-term complications were not different between the two arms. CONCLUSIONS: Patients with cervical cancer with uterine perforations may be able to safely proceed with brachytherapy treatment without delay or need for prophylactic antibiotics in the acute setting. Further validating data would be able to assist in establishing a new standard of care and help prevent unnecessary and harmful breaks during treatment.

Repurposing Kir6/SUR2 Channel Activator Minoxidil to Arrests Growth of Gynecologic Cancers.

Gynecologic cancers are among the most lethal cancers found in women, and, advanced stage cancers are still a treatment challenge. Ion channels are known to contribute to cellular homeostasis in all cells and mounting evidence indicates that ion channels could be considered potential therapeutic targets against cancer. Nevertheless, the pharmacologic effect of targeting ion channels in cancer is still understudied. We found that the expression of Kir6.2/SUR2 potassium channel is a potential favorable prognostic factor in gynecologic cancers. Also, pharmacological stimulation of the Kir6.2/SUR2 channel activity with the selective activator molecule minoxidil arrests tumor growth in a xenograft model of ovarian cancer. Investigation on the mechanism linking the Kir6.2/SUR2 to tumor growth revealed that minoxidil alters the metabolic and oxidative state of cancer cells by producing mitochondrial disruption and extensive DNA damage. Consequently, application of minoxidil results in activation of a caspase-3 independent cell death pathway. Our data show that repurposing of FDA approved K+ channel activators may represent a novel, safe adjuvant therapeutic approach to traditional chemotherapy for the treatment of gynecologic cancers.

Salvage treatment in recurrent endometrial cancer of the pelvis and peritoneal cavity.

Regional recurrence of endometrial cancer is a challenging yet potentially curable group of patients without defined standard of care. Our aim is to determine optimal methods of salvage therapy for regionally recurrent endometrial cancer. Twenty-two cases of nodal, pelvic, or peritoneal cavity recurrences of endometrial cancer were identified from a single institution database. Univariable Cox proportional hazards models were used to estimate the risk of a second recurrence or death. Kaplan-Meier plots were used to estimate the probability of progression free survival and overall survival among patients in three cohorts: Multimodality therapy (surgery, chemotherapy, and external beam radiotherapy [EBRT] +/- vaginal brachytherapy), non-surgery (chemotherapy or EBRT, or both), and surgery cohort (surgery +/- chemotherapy OR EBRT). Thirteen recurrences (59%) were regional including the pelvic and paraaortic nodes, while nine recurrences (41%) were abdominal. For the entire cohort, the probability of progression free survival at 2 years was 51% (95% CI, 26% - 72%). The 2-year probability of progression free survival was 62% in the multimodality cohort, 40% in the non-surgery cohort, and 38% in the surgery cohort. The 2-year probability of overall survival was 69% (95% CI, 38% - 86%) across our population. At 40 months of follow up, the only living patients belonged to the multimodality cohort. We found no significant association of a definitive salvage regimen for recurrent endometrial cancer of the pelvis and peritoneal cavity. Aggressive use of multimodality therapy with surgery followed by tumor-directed radiotherapy and chemotherapy offers potentially curative therapy for these patients.

Does adjuvant concurrent or sequential chemotherapy increase the radiation-related toxicity of vaginal brachytherapy for endometrial cancer patients?

PURPOSE: To compare radiation toxicity in endometrial cancer patients treated with adjuvant vaginal brachytherapy (VBT) vs. VBT with concurrent chemotherapy (CCT) or sequential chemotherapy (SCT) METHODS: We retrospectively analyzed 131 patients with endometrial cancer treated with VBT without external beam radiation therapy. Toxicities were graded according to the Common Terminology Criteria for Adverse Events v4.03. CCT was defined as VBT delivered between the first and last cycle of chemotherapy (CT); SCT was defined as VBT delivered before or after CT. RESULTS: Median followup was 36 months, with a 3-year survival rate of 88%. Of the 131 patients, 92 were treated with VBT alone, 34 with VBT and CCT, and 5 with VBT and SCT. The most common toxicity was vaginal stricture, with 30 (22.9%) patients affected. The distribution of toxicities was vaginal 28%, urinary 12%, rectal 11%, and fatigue 5%; none greater than Grade 2. Compared with patients treated with VBT alone, the addition of CT did not increase the chance of vaginal stricture formation (p = 0.84). The difference in system-specific toxicities between treatment modalities was not statistically significant. CONCLUSION: The most common pelvic toxicity from VBT is vaginal stenosis with other toxicities being infrequent and generally Grade 1. The addition of CT in a sequential or concurrent fashion did not increase the rate of pelvic toxicity from VBT alone.

Early outcomes and impact of a hybrid IC/IS applicator for a new MRI-based cervical brachytherapy program.

PURPOSE: The purpose of this study was to report early outcomes and assess the learning curve in a new MRI-based cervical brachytherapy program. METHODS: We accrued 33 patients prospectively, and only patients with ≥3 months' followup (n = 27) were assessed for disease control and toxicity. Eras were defined as first half and second half for the intracavitary (IC)-only era (n = 13 each), and the intracavitary/interstitial (IC/IS) era was separated by difference in applicator availability (n = 7). Dose to 90% of the high-risk clinical target volume (D90 HR-CTV) and minimum dose to the maximally irradiated 2 cubic centimeters (D2cc) to organs at risk were used to assess dosimetry. Statistics were performed with t tests and Kaplan-Meier method. RESULTS: Median followup was 14.7 months. Median treatment duration was 50.5 vs. 57 days for patients treated with external beam radiation therapy at our institution vs. an outside institution (p = 0.03). One-year local control, noncervical pelvic control, distant metastasis-free rate, and overall survival were 84.0%, 96.0%, 78.5%, and 91.3%, respectively. When comparing the first half and second half eras of IC only, there were no differences in median D90 HR-CTV or D2cc of the bladder, rectum, or sigmoid. Comparing the entire IC era to the IC/IS era, median D90 HR-CTV trended higher from 88.0 Gy to 92.9 Gy (p = 0.11). D2cc rectum decreased from 69.3 Gy to 62.6 Gy (p = 0.01), and D2cc bladder trended lower from 87.5 Gy to 83.6 Gy (p = 0.09). CONCLUSIONS: There was no significant difference between the first half and second half eras with IC-only MRI-based brachytherapy. Incorporation of an IC/IS applicator generated the greatest dosimetric improvement. Early results of the MRI-based brachytherapy program are favorable.

Comparison of dosimetric and clinical outcomes between short- and long-channel cylinder applicators for vaginal brachytherapy in intermediate- and high-risk endometrial cancer.

PURPOSE: Vaginal brachytherapy (VBT) using a cylinder applicator is a standard treatment of intermediate- and high-risk endometrial cancer. We conducted a retrospective study of the dosimetric and clinical outcomes at our institution with 2 single-channel applicators in patients receiving VBT. METHODS AND MATERIALS: One hundred thirty-six patients with endometrial cancer treated from 2006 to 2016 receiving VBT after definitive surgery were evaluated. Two cylinders were used with the distal dwell position 7.1-12.8 mm from the apex varying by diameter (short channel), and 3.2 mm from the apex (long channel). We prescribed 18-26 Gy in 3-4 fractions at 0.5 cm depth. Measurements of the distance from the apex to the prescription isodose line were taken from CT imaging. Student's t test and the Wilcoxon rank-sum test were used with corrections for multiple comparisons. RESULTS: Patients had International Federation of Gynecology and Obstetrics 2009 Stage I-II disease (70 Stage IA, 58 Stage IB, 9 Stage II). Mean cylinder apex dose was 95.2% and 154.7% of prescription (p < 0.001), and mean distance from apex to the prescription isodose line was 0.54 mm and 3.5 mm (p < 0.001) for the short- and long-channel cylinders, respectively. There were no significant differences in any toxicity between cylinders. Four patients (2.9%) had vaginal recurrence, all of whom were treated with the short-channel cylinder. Cylinder type was not associated with vaginal recurrence (p = 0.27). CONCLUSIONS: A cylinder applicator with a distal dwell position closer to the apex results in higher doses to the vaginal cuff and increased D2cc to the bladder. All four recurrences were in the short-channel cylinder. Additional investigation into applicator design and impact on patient outcomes in larger cohorts with sufficient followup is warranted.

Adjuvant External Radiation Impacts Outcome of Pelvis-limited Stage III Endometrial Carcinoma: A Multi-institutional Study.

BACKGROUND: Adjuvant therapy choice for women with FIGO stage III endometrial carcinoma (EC) is controversial. We investigate the comparative benefit of adjuvant chemotherapy (CT) alone, radiation therapy alone (RT) or in combination (chemotherapy and radiation therapy [CRT]) with respect to recurrence-free survival (RFS) and overall survival (OS) in women with pelvis-limited (PL) EC (stage IIIA, IIIB, and IIIC1). MATERIALS AND METHODS: A multi-institutional database of 270 surgically staged women with PLEC was analyzed. Univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify factors associated with RFS and OS. RESULTS: Median RFS and OS were 112 and 130 months, respectively, for the full cohort. Adjuvant treatment was CT in 21%, RT in 27%, and CRT in 47%. Age, year of treatment, grade, histology, and adjuvant treatment were significantly associated with RFS and OS on univariate analysis. PLEC patients receiving CT alone fared worse in terms of RFS (P=0.07 relative to RT and <0.01 relative to CRT). On MVA, CRT retained significantly improved RFS relative to CT (hazard ratio for recurrence 0.38, P<0.01). PLEC patients receiving RT or CRT had improved OS compared with CT, P<0.01 and 0.03, respectively. On MVA, both RT only and CRT retained association with improved OS relative to CT alone (hazard ratio for death, 0.43, P=0.02 and 0.40, P<0.01, respectively). CONCLUSIONS: For surgically staged PL stage III EC, treatment regimens incorporating RT were associated with improved survival endpoints relative to CT alone. As such, RT should be considered an important component in the adjuvant management of stage III PLEC.

How one institution overcame the challenges to start an MRI-based brachytherapy program for cervical cancer.

PURPOSE: Adaptive magnetic resonance imaging (MRI)-based brachytherapy results in improved local control and decreased high-grade toxicities compared to historical controls. Incorporating MRI into the workflow of a department can be a major challenge when initiating an MRI-based brachytherapy program. This project aims to describe the goals, challenges, and solutions when initiating an MRI-based cervical cancer brachytherapy program at our institution. MATERIAL AND METHODS: We describe the 6-month multi-disciplinary planning phase to initiate an MRI-based brachytherapy program. We describe the specific challenges that were encountered prior to treating our first patient. RESULTS: We describe the solutions that were realized and executed to solve the challenges that we faced to establish our MRI-based brachytherapy program. We emphasize detailed coordination of care, planning, and communication to make the workflow feasible. We detail the imaging and radiation physics solutions to safely deliver MRI-based brachytherapy. The focus of these efforts is always on the delivery of optimal, state of the art patient care and treatment delivery within the context of our available institutional resources. CONCLUSIONS: Previous publications have supported a transition to MRI-based brachytherapy, and this can be safely and efficiently accomplished as described in this manuscript.

Self epitopes shared between human skeletal myosin and Streptococcus pyogenes M5 protein are targets of immune responses in active juvenile dermatomyositis.

OBJECTIVE: To identify self T cell epitopes associated with proinflammatory immune responses and clinically active juvenile dermatomyositis (juvenile DM). The target of our search for relevant epitopes was represented by amino acid sequences shared between human skeletal myosin and Streptococcus pyogenes M5 protein. The long-term objective of the project is to identify suitable targets for immunotherapy of the disease. METHODS: We used computerized algorithms to identify putative agretopes on both the human myosin and Streptococcus M5 proteins. Direct binding assays for homolog peptides were used to confirm such predictions. Antigenicity and functional cross-reactivity were evaluated by cytotoxicity assays and by measurement of cytokine levels. Specific T cells were isolated by T cell capture, and T cell receptor (TCR) V(beta) gene usage was identified by reverse transcriptase-polymerase chain reaction. RESULTS: We identified peptides that are targets of disease-specific cytotoxic T cell responses. T cell reactivity against the self peptides correlates with clinical signs of early, active myositis. Such reactivity is accompanied by production of proinflammatory cytokines, which may contribute to the damage. T cell cross-recognition of bacterial and human homologs was shown functionally as well as by sorting peptide-specific T cells and identifying oligoclonal and largely overlapping TCR V(beta) gene usage. CONCLUSION: These findings represent the first identification of a self epitope in juvenile DM, providing a potential candidate for antigen-specific immune therapy.