Management and long-term clinical outcomes of patients with stage IVA cervical cancer with bladder involvement.

OBJECTIVE: To describe the long-term outcomes of patients with stage IVA cervical cancer, a rare and deadly disease for which long-term toxicity data are scarce, to guide clinician counseling and survivorship support. METHODS: In a retrospective review of a prospectively maintained database, we identified 76 patients with stage IVA cervical cancer with biopsy- or MRI-proven bladder mucosal involvement who received definitive radiotherapy (external beam radiotherapy [EBRT] alone or EBRT plus brachytherapy) with or without chemotherapy at our institution between 2000 and 2020. We used Kaplan-Meier modeling to estimate recurrence-free survival (RFS) and overall survival (OS) and used proportional hazard modeling to identify clinical variables associated with recurrence or survival. We performed actuarial competing risk modeling for severe late toxicity (grades 3 to 5, occurring >6 months of follow-up) and vesicovaginal fistulae (VVF), censoring for pelvic recurrence and death, and made comparisons between potential predictors using Gray's test and binary logistic regression. RESULTS: The median follow-up time was 76 months (interquartile range 58-91). The median OS duration was 35 months (range, 18-not reached), and the 2- and 5-year OS rates were 53.6% and 40.9%, respectively. OS and RFS did not differ significantly between patients who received EBRT alone (N = 18) or EBRT plus brachytherapy (N = 49). Current smoking was a strong predictor of severe late toxicity, whose incidence was 14% at 2 years and 17% at 10 years. The VVF incidence was 24% at 2 years and 32% at 10 years. CONCLUSION: Patients with stage IVA cervical cancer, even those who receive EBRT alone, can have long-term survival. These patients should be followed closely for late radiation-related toxicity.

Long-term survival following definitive radiation therapy for recurrence or oligometastases in gynecological malignancies: A landmark analysis.

OBJECTIVE: Radiation therapy (RT) may improve outcomes for patients with oligometastatic cancer. We sought to determine if there are long-term survivors treated with definitive RT for recurrent or oligometastatic gynecological cancer (ROMGC), and to evaluate the clinical and disease characteristics of these patients. METHODS: We performed a landmark analysis in 48 patients with ROMGC who survived for ≥5 years following definitive RT of their metastasis. Patient characteristics were extracted from the medical record. DFS was modeled using the Kaplan-Meier method. RESULTS: This cohort included 20 patients (42%) with ovarian cancer, 16 (33%) with endometrial cancer, 11 (23%) with cervical cancer, and one (2%) with vaginal cancer. The sites of ROMGC were the pelvic (46%), para-aortic (44%), supraclavicular (7%), mediastinal (4%), axillary (4%) lymph nodes and the lung (5.5%). Median total RT dose and fractionation were 62.1 Gy and 2.1 Gy/fraction; one patient was treated with SBRT. 32 patients (67%) received chemoradiation; these patients had higher rates of median DFS than those treated with RT alone (93 vs. 34 months, P = 0.05). At median follow-up of 11.7 years, 11 (23%) patients had progression of disease. 20 (42%) patients had died, 9 (19%) died from non-gynecologic cancer and 8 (17%) from gynecologic cancer (three were unknown). 25 (52%) patients were alive and disease-free (10 initially had endometrial cancer [63% of these patients], eight had cervical cancer [73%], six had ovarian cancer [30%], one had vaginal cancer [100%]). CONCLUSIONS: Long-term survival is possible for patients treated with definitive RT for ROMG, however randomized data are needed to identify which patients derive the most benefit.

Premastectomy Radiotherapy and Immediate Breast Reconstruction: A Randomized Clinical Trial.

Importance: Premastectomy radiotherapy (PreMRT) is a new treatment sequence to avoid the adverse effects of radiotherapy on the final breast reconstruction while achieving the benefits of immediate breast reconstruction (IMBR). Objective: To evaluate outcomes among patients who received PreMRT and regional nodal irradiation (RNI) followed by mastectomy and IMBR. Design, Setting, and Participants: This was a phase 2 single-center randomized clinical trial conducted between August 3, 2018, and August 2, 2022, evaluating the feasibility and safety of PreMRT and RNI (including internal mammary lymph nodes). Patients with cT0-T3, N0-N3b breast cancer and a recommendation for radiotherapy were eligible. Intervention: This trial evaluated outcomes after PreMRT followed by mastectomy and IMBR. Patients were randomized to receive either hypofractionated (40.05 Gy/15 fractions) or conventionally fractionated (50 Gy/25 fractions) RNI. Main Outcome and Measures: The primary outcome was reconstructive failure, defined as complete autologous flap loss. Demographic, treatment, and outcomes data were collected, and associations between multiple variables and outcomes were evaluated. Analysis was performed on an intent-to-treat basis. Results: Fifty patients were enrolled. Among 49 evaluable patients, the median age was 48 years (range, 31-72 years), and 46 patients (94%) received neoadjuvant systemic therapy. Twenty-five patients received 50 Gy in 25 fractions to the breast and 45 Gy in 25 fractions to regional nodes, and 24 patients received 40.05 Gy in 15 fractions to the breast and 37.5 Gy in 15 fractions to regional nodes, including internal mammary lymph nodes. Forty-eight patients underwent mastectomy with IMBR, at a median of 23 days (IQR, 20-28.5 days) after radiotherapy. Forty-one patients had microvascular autologous flap reconstruction, 5 underwent latissimus dorsi pedicled flap reconstruction, and 2 had tissue expander placement. There were no complete autologous flap losses, and 1 patient underwent tissue expander explantation. Eight of 48 patients (17%) had mastectomy skin flap necrosis of the treated breast, of whom 1 underwent reoperation. During follow-up (median, 29.7 months [range, 10.1-65.2 months]), there were no locoregional recurrences or distant metastasis. Conclusions and Relevance: This randomized clinical trial found PreMRT and RNI followed by mastectomy and microvascular autologous flap IMBR to be feasible and safe. Based on these results, a larger randomized clinical trial of hypofractionated vs conventionally fractionated PreMRT has been started (NCT05774678). Trial Registration: ClinicalTrials.gov Identifier: NCT02912312.

Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy.

BACKGROUND: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. METHODS: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020-1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-ß/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. RESULTS: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2-50.2 fold-increase from baseline), frequency (1.2-1.7), rearrangements (1.2-40.2), and clonality (1.2-15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. CONCLUSION: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol.

PURPOSE: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. METHODS AND MATERIALS: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. RESULTS: The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. CONCLUSIONS: Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

Circulating neutrophils and tumor-associated myeloid cells function as a powerful biomarker for response to chemoradiation in locally advanced cervical cancer.

Purpose: The immune system's role in mediating the cytotoxic effects of chemoradiotherapy remains not completely understood. The integration of immunotherapies into treatment will require insight into features and timing of the immune microenvironment associated with treatment response. Here, we investigated the role of circulating neutrophils and tumor-associated myeloid cells (TSAMs) as potential agents and biomarkers for disease-related outcomes in locally advanced cervical cancer (LACC). Material and Methods: Hematologic parameters for two LACC patient cohorts, a retrospective clinical and a prospective translational cohort, were obtained at baseline, weekly during chemoradiotherapy for the retrospective cohort, biweekly during chemoradiotherapy for the prospective cohort, and at the first follow-up visit for both cohorts (mean 14.7 weeks, range 8.1-25.1 weeks for the prospective cohort and 5.3 weeks with a range of 2.7-9.0 weeks for the retrospective cohort). In both cohorts, baseline as well as mean and lowest on-treatment values for platelets, hemoglobin, absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) were analyzed for correlations with disease-related outcomes. In the prospective cohort, circulating myeloid cells were isolated from peripheral blood mononuclear cells (PBMCs), and TSAMs were isolated from tumor tissue via a novel serial cytobrush sampling assay. The samples were analyzed by flow cytometry. Results: In both cohorts, the only hematologic parameter significantly associated with survival was elevated on-treatment mean ANC (mANC), which was associated with lower local failure-free and overall survival rates in the retrospective and prospective cohorts, respectively. mANC was not associated with a difference in distant metastases. CD11b+CD11c- TSAMs, which act as a surrogate marker for intratumoral neutrophils, steadily decreased during the course of chemoRT and nadier'd at week 5 of treatment. Conversely, circulating myeloid cells identified from PBMCs steadily increased through week 5 of treatment. Regression analysis confirmed an inverse relationship between circulating myeloid cells and TSAMs at this time point. Conclusions: These findings identify on-treatment mean neutrophil count as a predictor of disease-related outcomes, suggest that neutrophils contribute to chemoradiation treatment resistance, and demonstrate the importance of techniques to measure intratumoral immune activity.

Locoregional Management and Prognostic Factors in Breast Cancer With Ipsilateral Internal Mammary and Axillary Lymph Node Involvement.

PURPOSE: Patients with breast cancer and ipsilateral axillary and internal mammary (IM) lymph node involvement (cN3b) often forgo IM node resection. Therefore, radiation is important for curative therapy. However, prognosis is not well described in the era of modern systemic therapy, and limited data exist to guide optimal locoregional treatment recommendations. METHODS AND MATERIALS: We retrospectively reviewed 117 patients with nonmetastatic cN3b breast cancer treated at our institution between 2014 and 2019. Staging included ultrasound evaluation of all regional nodal basins. All patients received neoadjuvant chemotherapy, resection of the breast primary, and axillary nodal dissection, followed by adjuvant radiation to the breast/chest wall and regional nodes. Institutional guidelines recommend a 10-Gy boost to radiographically resolved nodes, and a 16-Gy boost to unresolved nodes. Overall survival, recurrence-free survival (RFS), locoregional RFS, internal mammary RFS, and distant metastasis-free survival were evaluated with Kaplan-Meier analysis. A multivariable model for RFS was constructed. RESULTS: Median follow-up for 117 patients was 3.82 years. Median age at diagnosis was 46 years and 56 patients (48%) were receptor group ER+/HER2-. Mastectomy was performed in 96 patients (82%), 38 (32%) had biopsy-confirmed IMC involvement, and 8 (7%) had IM node dissection. The median initial radiation dose was 50 Gy (range, 50-55 Gy) and IMC boost 10 Gy (range, 0-16 Gy). The 5-year overall survival, IM RFS, locoregional RFS, distant metastasis-free survival, and RFS were 74%, 98%, 89%, 68%, and 67%, respectively. On multivariable analysis, a clinical complete response of the IM nodes or ypN0 (pathologic complete response of nodes) status had improved 5-year RFS with hazard ratios of 0.24 (P = .006) and 0.27 (P = .05), respectively. Extranodal extension or lymphovascular invasion were associated with worse 5-year RFS with hazard ratios of 4.13 (P = .001) and 2.25 (P = .04), respectively. CONCLUSIONS: Multimodality therapy provides excellent locoregional control of 89% at 5 years for patients with cN3b breast cancer. Adjuvant radiation yields a 5-year IM RFS of 98%. Clinical and pathologic response of IM nodes are independently prognostic for RFS.

A new development in ultrasound-compatible gynecologic brachytherapy simulators.

PURPOSE: Gynecologic brachytherapy is an essential component in the curative treatment of cervical cancer. With the decline in brachytherapy utilization, gynecologic brachytherapy simulators are being used to provide a mechanism to enhance proficiency-based resident training. However, most models that have been used lack procedural fidelity as they are either repurposed from OB/GYN basic models or from physics phantoms. Therefore, we set out to develop a high-fidelity, ultrasound- and CT-compatible gynecologic brachytherapy training simulator. METHODS AND MATERIALS: Based on prior experience with gynecologic training simulators on the market, we developed a wish list for an ultrasound-compatible brachytherapy training model. A custom simulator was developed based on an existing pelvic ultrasound trainer. Features included a cervical os and endometrial canal as well as a palpable and hypoechoic cervical tumor. RESULTS: The model took about 3 months from the initial meeting with the developer to completion. The properties of the material were equivalent to water for ultrasound, CT, and also MRI and the model did not show signs of degradation after multiple tandem insertions. CONCLUSIONS: A high-fidelity ultrasound-compatible simulator was effectively developed and utilized to improve resident training to perform brachytherapy implants with a derivative benefit in the long term of improving survival for women with advanced gynecologic malignancies through having access to more proficient brachytherapists. Future directions include enhancing the model to allow for repetitive needle insertion and suturing for interstitial training as well as creating variations in anatomy (e.g., retroverted uterus, bulky tumors, etc.) for more advanced technical training.

Developing an intraoperative 3T MRI-guided brachytherapy program within a diagnostic imaging suite: Methods, process workflow, and value-based analysis.

PURPOSE: We integrated a brachytherapy procedural workflow within an existing diagnostic 3.0-T (3T) MRI suite. This setup facilitates intraoperative MRI guidance for optimal applicator positioning, particularly for interstitial needle placements in gynecologic cases with extensive parametrial involvement. METHODS AND MATERIALS: Here we summarize the multidisciplinary collaboration, equipment, and supplies necessary to implement an intraoperative MRI-guided brachytherapy program; outline the operational workflow via process maps; and address safety precautions. We evaluate internal resource utilization associated with this progressive approach via time-driven activity-based costing methodology, comparing institutional costs to that of a traditional workflow (within a CT suite, followed by separate postprocedure MRI) over a single brachytherapy procedural episode. RESULTS: Resource utilization was only 15% higher for the intraoperative MRI-based workflow, attributable to use of the MRI suite and increased radiologist effort. Personnel expenses were the greatest cost drivers for either workflow, accounting for 76-77% of total resource utilization. However, use of the MRI suite allows for potential cost-shifting opportunities from other resources, such as CT, during the procedural episode. Improvements in process speed can also decrease costs: for each 10% decrease in case duration from baseline procedure time, total costs could decrease by roughly 8%. CONCLUSIONS: This analysis supports the feasibility of an intraoperative MRI-guided brachytherapy program within a diagnostic MRI suite and defines many of the resources required for this procedural workflow. Longer followup will define the full utility of this approach in optimizing the therapeutic ratio for gynecologic cancers, which may translate into lower costs and higher value with time, over a full cycle of care.

Clinical utility and value contribution of an MRI-positive line marker for image-guided brachytherapy in gynecologic malignancies.

PURPOSE: The purpose of this study was to investigate the utility of a novel MRI-positive line marker, composed of C4:S (cobalt chloride-based contrast agent) encapsulated in high-density polyethylene tubing, in permitting dosimetry and treatment planning directly on MRI. METHODS AND MATERIALS: We evaluated the clinical feasibility of the C4:S line markers in nine sequential brachytherapy procedures for gynecologic malignancies, including six tandem-and-ovoid and three interstitial cases. We then quantified the internal resource utilization of an intraoperative MRI-guided procedural episode via time-driven activity-based costing, identifying opportunities for cost-containment with use of the C4:S line markers. RESULTS: The C4:S line markers demonstrated the strongest positive signal visibility on 3D constructive interference in steady state (CISS)/FIESTA-C followed by T1-weighted sequences, permitting accurate delineation of the applicator lumen and thus the source path. These images may be fused along with traditional T2-weighted sequences for optimal tumor and anatomy contouring, followed by treatment planning directly on MRI. By eliminating postoperative CT for fusion and applicator registration from the procedural episode, use of the C4:S line markers could decrease workflow time and lower total delivery costs per procedure. CONCLUSIONS: This analysis supports the clinical utility and value contribution of the C4:S line markers, which permit accurate MRI-based dosimetry and treatment planning, thereby eliminating the need for postoperative CT for fusion and applicator registration.

Accelerated partial breast irradiation: Past, present, and future.

Accelerated partial breast irradiation (APBI) focuses higher doses of radiation during a shorter interval to the lumpectomy cavity, in the setting of breast conserving therapy for early stage breast cancer. The utilization of APBI has increased in the past decade because of the shorter treatment schedule and a growing body of outcome data showing positive cosmetic outcomes and high local control rates in selected patients undergoing breast conserving therapy. Technological advances in various APBI modalities, including intracavitary and interstitial brachytherapy, intraoperative radiation therapy, and external beam radiation therapy, have made APBI more accessible in the community. Results of early APBI trials served as the basis for the current consensus guidelines, and multiple prospective randomized clinical trials are currently ongoing. The pending long term results of these trials will help us identify optimal candidates that can benefit from ABPI. Here we provide an overview of the clinical and cosmetic outcomes of various APBI techniques and review the current guidelines for selecting suitable breast cancer patients. We also discuss the impact of APBI on the economics of cancer care and patient reported quality of life.

Management of anal cancer in the HIV-positive population.

Squamous cell anal cancer remains an uncommon entity; however, the incidence appears to be increasing in at-risk populations, especially those infected with human papillomavirus (HPV) and human immunodeficiency virus (HIV). Given the ability to cure this cancer using synchronous chemoradiotherapy, management practices of this disease are critical. This article considers treatment strategies for HIV-positive patients with anal cancer, including the impact on chemoradiation-induced toxicities and the role of highly active antiretroviral therapy in the treatment of this patient population. The standard treatment has been fluorouracil (5-FU) and mitomycin (or cisplatin) as chemotherapy agents plus radiation. Consideration to modifying the standard treatment regime is based on the fact that patients with HIV tend to experience greater toxicity, especially when CD4 counts are below 200; these patients also require longer treatment breaks. Additional changes to the chemotherapy dosing, such as giving 5-FU continuously and decreasing mitomycin dose, are evaluated and considered in relation to radiation field sizes in an effort to reduce toxicity, maintain local tumor control, and limit need for colostomy. The opportunity for decreasing the radiation field size and using intensity-modulated radiation therapy (IMRT) is also considered, particularly in light of the fact that IMRT provides dose-sparing while maximizing target volume dose to involved areas. The impact of the immune system in patients with HIV and squamous cell carcinoma of the anus and the associated response to therapy remains unknown. Continued studies and phase III trials will be needed to test new treatment strategies in HIV-infected patients with squamous cell cancer of the anus to determine which treatment protocols provide the greatest benefits.