Marilyn Huang

MRI-Guided High–Dose-Rate Intracavitary Brachytherapy for Treatment of Cervical Cancer: The University of Pittsburgh Experience

PURPOSE Image-based brachytherapy is increasingly used for gynecologic malignancies. We report early outcomes of magnetic resonance imaging (MRI)-guided brachytherapy. METHODS AND MATERIALS Consecutive patient cases with FIGO stage IB1 to IVA cervical cancer treated at a single institution were retrospectively reviewed. All patients received concurrent cisplatin with external beam radiation therapy along with interdigitated high-dose-rate intracavitary brachytherapy. Computed tomography or MRI was completed after each application, the latter acquired for at least 1 fraction. High-risk clinical target volume (HRCTV) and organs at risk were identified by Groupe Européen de Curiethérapie and European SocieTy for Radiotherapy and Oncology guidelines. Doses were converted to equivalent 2-Gy doses (EQD2) with planned HRCTV doses of 75 to 85 Gy. RESULTS From 2007 to 2013, 128 patients, median 52 years of age, were treated. Predominant characteristics included stage IIB disease (58.6%) with a median tumor size of 5 cm, squamous histology (82.8%), and no radiographic nodal involvement (53.1%). Most patients (67.2%) received intensity modulated radiation therapy (IMRT) at a median dose of 45 Gy, followed by a median brachytherapy dose of 27.5 Gy (range, 25-30 Gy) in 5 fractions. At a median follow up of 24.4 months (range, 2.1-77.2 months), estimated 2-year local control, disease-free survival, and cancer-specific survival rates were 91.6%, 81.8%, and 87.6%, respectively. Predictors of local failure included adenocarcinoma histology (P<.01) and clinical response at 3 months (P<.01). Among the adenocarcinoma subset, receiving HRCTV D90 EQD2 ≥84 Gy was associated with improved local control (2-year local control rate 100% vs 54.5%, P=.03). Grade 3 or greater gastrointestinal or genitourinary late toxicity occurred at a 2-year actuarial rate of 0.9%. CONCLUSIONS This study constitutes one of the largest reported series of MRI-guided brachytherapy in North America, demonstrating excellent local control with acceptable morbidity. Dose escalation may be warranted when feasible for adenocarcinomas to offset the risk of local failure.

Definitive salvage for vaginal recurrence of endometrial cancer: The impact of modern intensity-modulated-radiotherapy with image-based HDR brachytherapy and the interplay of the PORTEC 1 risk stratification

PURPOSE Data for salvage radiotherapy for recurrent endometrial cancer are limited especially in the era of modern radiotherapy including IMRT and 3-dimensional image-based HDR brachytherapy. Theoretically, modern radiotherapy reduces the dose to critical organs-at-risk and maximizes dose to the target volume, possibly decreasing morbidity and increasing tumor control. MATERIALS AND METHODS Forty-one patients completing definitive salvage radiotherapy for vaginal recurrence of endometrial cancer from June 2004 to December 2013 were retrospectively reviewed. HDR Brachytherapy was completed using image-based planning with contouring/optimization with each fraction to a median dose of 23.75 Gy in 5 fractions. HDR brachytherapy was preceded by external beam radiotherapy predominately using an IMRT technique (90%) to a median dose of 45 Gy in 25 fractions. Toxicity was reported according to CTCAEv4. RESULTS At a median follow-up of 18 months (range: 3-78), the clinical complete response rate was 95%. The 3-year local control, distant control, recurrence free survival, and overall survival were 95%, 61%, 68%, and 67%. Significant predictors of both distant failure and overall survival were primary prognostic factors of depth of myometrial invasion, FIGO stage, and FIGO grade. There was no grade 3+ acute toxicity; the 3-year rate of grade 3+ late toxicity was 8%. CONCLUSIONS Salvage IMRT plus 3-dimensional image-based HDR brachytherapy shows excellent tumor control and minimal morbidity for vaginal recurrence of endometrial cancer. Anticipated salvage rates must be taken in the context of primary risk factors including depth of myometrial invasion, FIGO stage, and FIGO grade.

Endometrial histology in severely obese bariatric surgery candidates: an exploratory analysis

BACKGROUND Endometrial pathology risk has been linked to obesity; however, little is known of its prevalence in severely obese women not seeking care for endometrial pathology associated symptoms. This pilot study was designed to explore the frequency and risk factors associated with endometrial pathology in cancer-free, severely obese, bariatric surgery candidates using the Pipelle endometrial sampling technique (SureFlex Preferred Curette, Bioteque America, Inc, New Taipei City, Taiwan). METHODS Twenty-nine severely obese bariatric surgery candidates with intact uteruses and no history of endometrial cancer or endometrial ablation were included in this subanalysis from a larger cohort of 47. Endometrial samples were obtained using a Pipelle endometrial suction curette at a single time point before surgery. Logistic regression was used to assess the relationship between body mass index and endometrial pathology when adjusting for age and race. RESULTS Of the 29 successful biopsies, 8 (27.6%) were classified as abnormal endometrium: 1 was classified as complex atypical hyperplasia, 1 was classified as hyperplasia without atypia, 4 samples were identified with endometrial polyps, and 2 samples were identified with metaplasia. None presented with cancer. Increasing body mass index was significantly associated with higher risk of abnormal endometrium (OR = 1.19, 95% CI [1.03-1.36], P = .01). CONCLUSIONS The findings in this sample suggest that obesity may be associated with increased risk of having undiagnosed endometrial pathology. More thorough examination of relationships between levels of obesity and endometrial pathology are needed to better characterize high cancer risk groups who may benefit from introducing new screening measures.

Pelvic Exenteration: Impact of age on surgical and oncologic outcomes

OBJECTIVE To evaluate whether preoperative age impacts surgical outcomes, complication rates, and/or recurrence in women undergoing pelvic exenteration. METHODS All women who underwent a pelvic exenteration for any gynecologic indication at our institution from 1993 to 2010 were included. Women were stratified into groups based on age in years (young: ≤ 50, middle: 51-64, and senior: ≥ 65). Baseline characteristics, surgical outcomes, early (<60 days) and late (≥ 60 days) postoperative complications, and recurrence/survival outcomes were ascertained. Fishers exact test or Kruskal-Wallis test was performed. Kaplan-Meier survival curves were compared. RESULTS 161 patients were included (58 young, 62 in the middle, and 41 senior). Women in the young group predominately had a diagnosis of cervical cancer (82.8%) while women in the senior group primarily had a diagnosis of vulvar or vaginal cancer (70.7%). Senior women were also more likely to have hypertension (p < 0.0001) and pulmonary disease (p = 0.040). Operative time was significantly shorter for women in the senior group (8.5h) compared with the middle (9.5h) and young group (10.1h) (p = 0.0089). There were no significant differences in early or late complications when stratified by age. The overall survival did not differ between age groups (p = 0.3760). CONCLUSION Although hypertension and pulmonary disease were more frequent in the senior age group, duration of surgery, blood loss, length of hospital stay and complication rates did not increase with age. Advanced chronological age should not be considered a contraindication to a potentially curative surgical procedure.

Image-based multichannel vaginal cylinder brachytherapy for vaginal cancer.

PURPOSE To investigate the clinical feasibility and treatment outcomes of image-based high-dose-rate (HDR) brachytherapy using an intracavitary multichannel vaginal cylinder for the definitive treatment of vaginal cancers. METHODS AND MATERIALS A total of 41 patients with vaginal cancer (24% primary vaginal and 76% recurrence from other gynecologic primaries) treated with definitive radiotherapy ± chemotherapy including image-based HDR brachytherapy with a multichannel vaginal cylinder were included in the study. Image-based brachytherapy was completed using either CT- (41%) or MR-based planning (59%) with each fraction. The high-risk clinical target volume was defined based on the pre- and postexternal beam radiotherapy gross tumor volume. Doses were converted to equivalent dose of 2Gy per fraction. Endpoints examined were dose-volume parameters and early clinical outcomes. RESULTS The median high-risk clinical target volume was 24.2 cc (interquartile range [IQR], 12.6), with a median dose to 90% (D90) of 77.1 Gy (IQR, 3.4). The median dose to 2 cc (D(2 cc)) for the bladder, rectum, and sigmoid were 59.4 Gy (IQR, 5.6), 58.2 Gy (IQR, 4.1), and 52.3 Gy (IQR, 5.5), respectively. After a median followup of 16 months (range, 3-35), complete clinical response was documented in 98% of the patients. The 2-year local, regional, and distant control; and disease-free and overall survival were 93%, 100%, 81%, 78%, and 88%, respectively. The 2-year actuarial rate of late Grade 3 or higher toxicity was 4% overall with 0%, 0%, 0%, and 4% for vaginal, bladder, urethral, and gastrointestinal, respectively. CONCLUSIONS Image-based HDR brachytherapy using an intracavitary multichannel cylinder seems feasible in definitive vaginal cancer treatment. The described clinical implementation shows promising early clinical outcomes with high rates of local control and little toxicity, which should be validated with extended followup.

The effect of groin treatment modality and sequence on clinically significant chronic lymphedema in patients with vulvar carcinoma

Objective Chronic lymphedema (CL) after inguinal lymph node dissection (ILND) or radiotherapy (RT) is a significant problem for vulvar cancer survivors. The treatment modality or combination of therapies that poses the greatest risk is not known. The objective of this study was to describe rates of clinically significant CL conferred by different groin treatment modalities. Methods Medical records of vulvar cancer patients who had groin treatment with ILND, RT, or both were retrospectively reviewed. Each treated groin was considered individually, and divided into 4 treatment groups: ILND alone, ILND with adjuvant RT, neoadjuvant chemoradiation therapy (NCRT), or NCRT followed by ILND. Clinically significant CL was defined as that which required treatment and was recorded by laterality. Differences among groups were evaluated with χ2 and Fisher exact test. Results Between 2000 and 2010, 146 patients with vulvar cancer who underwent therapy to 1 or both groins were identified for a total of 266 treated groins. The rates of CL for single-modality treatment, ILND or NCRT, were 10.9% and 6.7%, respectively. Multimodal treatment resulted in higher rates of CL, 13.5% for ILND followed by RT and 17.2% for NCRT followed by ILND, although differences were not significant (P = 0.37). Conclusions Clinically significant CL was not different between treatment modalities in this study, but is underpowered. The results provide valuable information about treatment complications that will be useful for patient-centered counseling. Prospective evaluation of CL and its impact on quality of life is warranted.

Neoadjuvant radiotherapy with or without chemotherapy followed by extrafascial hysterectomy for locally advanced endometrial cancer clinically extending to the cervix or parametria

PURPOSE For locally-advanced uterine cancer clinically extending to the cervix, two treatment paradigms exist: surgical staging radical hysterectomy with tailored adjuvant therapy or neoadjuvant therapy followed by a less extensive simple hysterectomy. Currently, insufficient data exists to guide consensus guidelines and practical application of preoperative radiotherapy. MATERIALS AND METHODS Retrospective IRB approved cohort study from 1999 to 2014 of 36 endometrial cancer patients with clinical involvement of cervix±parametria treated with neoadjuvant external beam radiotherapy (45-50.4Gy in 25-28 fractions) and image-based HDR brachytherapy (5-5.5Gy times 3-4 fractions)±chemotherapy followed by extrafascial hysterectomy performed at a median of 6weeks after radiotherapy. RESULTS All patients had clinical cervical extension, 50% also had parametria extension, and 31% had nodal involvement. At the time of surgery 91% had no clinical cervical involvement, 58% had no pathologic cervical involvement, and all had margin negative resection. The pathologic complete response rate was 24%. Median follow-up from the time of surgery was 20months (range: 0-153). The 3-year local control, regional control, distant control, disease free survival and overall survival rates were 96%, 89%, 84%, 73%, and 100%. The 3-year rate of grade 3 complications was 11%, with no grade 4+ toxicity. CONCLUSIONS Neoadjuvant radiation therapy±chemotherapy followed by extrafascial hysterectomy appears to be a viable option for patients with endometrial cancer clinically extending to the cervix and parametria. The HDR brachytherapy schema of 5-5.5Gy times 3-4 fractions, for a cumulative EQD2 of 60-70Gy, is well tolerated with high rates of clinical and pathological response.

Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancers: is there a role?

BACKGROUND Hyperthermic intraperitoneal chemotherapy (HIPEC) is often used to treat gastrointestinal malignancies and is of interest in epithelial ovarian cancer (EOC) given the propensity for intraperitoneal spread. The role of HIPEC in the treatment of gynecologic malignancies is not well defined. We sought to describe clinical characteristics and outcomes of our patient population treated with HIPEC. METHODS IRB approval was obtained. Patients diagnosed with EOC and treated with HIPEC from January 2007 until December 2013 were identified using a prospectively maintained HIPEC database. Patient charts were abstracted to identify patient demographic information, treatment characteristics, and outcome data. Statistical analysis was descriptive. RESULTS Thirty-four patients were identified. Mean age at diagnosis was 56.5 years. The majority of cases (28, 82%) were of serous histology. The indications for HIPEC administration were as follows: 9% primary treatment, 41% first recurrence, 26% second recurrence, and 24% consolidative therapy in the setting of primary or recurrent disease. The majority of patients (21, 62%) received mitomycin C. The other drugs administered include cisplatin (10, 29%), oxaliplatin (2, 6%), and carboplatin (1, 3%). Mean length of hospital stay was 9 days (range, 3-39 days). The rates of postoperative bacteremia and hematologic toxicity were 6% and 54%, respectively. Seven (21%) patients developed transient renal dysfunction, and this was seen almost exclusively in the patients who received cisplatin. One (3%) additional patient had renal dysfunction that persisted longer than 30 days post-operative but did not go on to require dialysis. There were no perioperative deaths in this cohort. Eleven (32%) patients received additional chemotherapy following HIPEC administration. At a median follow-up of 20 months (range, 3-87 months), eight patients are alive with disease, seven have no evidence of disease, 14 have died of their disease, and five patients have been lost to follow-up. CONCLUSIONS This data supports a reasonable side effect profile of treatment of EOC with HIPEC. Prospective studies are needed to elucidate the optimal drug and patient population that would derive the most benefit from treatment with HIPEC.

Inguinal nodal region radiotherapy for vulvar cancer: Are we missing the target again?

The GROINSS-V II trial, in which NRG is also participating, is an ongoing observational study. As part of definitive therapy, patients with vulvar cancer undergo sentinel lymph node biopsy (SLNB) followed by observation if SLNB is negative or radiotherapy if SLNB is positive. Chemotherapy is at the discretion of the treating institution. Radiation is to be delivered to the bilateral inguinal nodes and the lower half of the external iliac nodes (though can be delivered only ipsilaterally at the discretion of the treating physician if the primary is well lateralized and there is no sign of a sentinel node on the contralateral side). The interim analysis of the ongoing GROINSS-V II trial showed a recurrence in 12.2% (10/82) of patients treated with radiation in the setting of positive sentinel lymph node biopsy [1]. On subset analysis the risk of nodal recurrence was 2.2% for micrometastases (≤2 mm) and 20% for macrometastases. Based on these early results, the study was modified to allow RT only for micrometastases and patients withmacrometastases now go on to receive completion inguinal dissection followed by possible adjuvant RT. When compared to single institution retrospective data for prophylactic groin RT [2,3], this failure rate appears to be on the higher side and raises the question of whether the outcomes seen in GROINSSV II speak more to the biology of disease in this group of patients or to a geographical miss with radiotherapy. When considering this, we were compelled to examine the radiation technique in this trial protocol as compared to historical techniques and current recommendations. In an early attempt to investigate the role of radiation therapy in the setting of vulvar cancer as a potentialmethod to decrease themorbidity associated with inguinal lymph node dissection, GOG 88 randomized patients with stage IB-III, cN0, vulvar cancer status post radical vulvectomy to either bilateral inguinal radiation or bilateral inguinal lymph node dissection followed by radiation to the pelvic and inguinal nodal regions if the dissection was positive [4]. This trial showed a greater number of inguinal recurrences in the radiation arm, however the radiation technique was poor and delivered an inadequate dose to the region at risk. In GOG 88 radiation was delivered without a CT scan for planning. This resulted in twodisadvantages. First, the risk of lymphnode involvement was not assessed and thus patients may indeed have had macroscopic disease for which 50 Gy is not sufficient. Second, the precise

Intra-thoracic cytoreduction of stage IV peritoneal malignancy : A case series

BACKGROUND Women with ovarian cancer primarily present with advanced intra-abdominal disease, frequently involving the diaphragm. CASES We present 2 cases of combined planned intra-thoracic and abdominopelvic radical cytoreduction for stage IV peritoneal malignancy. CONCLUSIONS Our case report indicates the importance of a multi-disciplinary approach in treating patients with advanced-stage peritoneal disease. Multi-disciplinary surgical procedures can achieve optimal cytoreduction and possibly improve overall survival.