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.

Acute and long-term toxicity of whole pelvis proton radiation therapy for definitive or adjuvant management of gynecologic cancers.

OBJECTIVE: To characterize long-term toxicity and disease outcomes with whole pelvis (WP) pencil beam scanning proton radiation therapy (PBS PRT) for gynecologic malignancies. METHODS: We reviewed 23 patients treated from 2013 to 2019 with WP PBS PRT for endometrial, cervical, and vaginal cancer. We report acute and late Grade (G)2+ toxicities, graded by Common Terminology Criteria for Adverse Events, Version 5. Disease outcomes were assessed by Kaplan-Meier method. RESULTS: Median age was 59 years. Median follow up was 4.8 years. 12 (52.2%) had uterine cancer, 10 (43.5%) cervical, 1 (4.3%) vaginal. 20 (86.9%) were treated post-hysterectomy. 22 (95.7%) received chemotherapy, 12 concurrently (52.2%). The median PBS PRT dose was 50.4GyRBE (range, 45-62.5). 8 (34.8% had para-aortic/extended fields. 10 (43.5%) received brachytherapy boost. Median follow up was 4.8 years. 5-year actuarial local control was 95.2%, regional control 90.9%, distant control 74.7%, both disease control and progression-free survival 71.2%. Overall survival was 91.3%. In the acute period, 2 patients (8.7%) had G2 genitourinary (GU) toxicity, 6 (26.1%) had gastrointestinal (GI) G2-3 toxicity, 17 (73.9%) had G2-4 hematologic (H) toxicity. In the late period, 3 (13.0%) had G2 GU toxicity, 1 (4.3%) had G2 GI toxicity, 2 (8.7%) had G2-3H toxicity. The mean small bowel V15Gy was 213.4 cc. Mean large bowel V15 Gy was 131.9 cc. CONCLUSIONS: WP PBS PRT for gynecologic malignancies delivers favorable locoregional control. Rates of GU and GI toxicity are low. Acute hematologic toxicity was most common, which may be related to the large proportion of patients receiving chemotherapy.

Perspectives of Zambian Clinical Oncology Trainees in the MD Anderson and Zambia Virtual Clinical Research Training Program (MOZART).

BACKGROUND: African countries are underrepresented in cancer research, partly because of a lack of structured curricula on clinical research during medical education. To address this need, the MD Anderson and Zambia Virtual Clinical Research Training Program (MOZART) was developed jointly by MD Anderson Cancer Center (MDA) and the Cancer Diseases Hospital in Zambia (CDH) for Zambian clinical oncology trainees. We explored participant perspectives to provide insight for implementation of similar efforts. MATERIALS AND METHODS: The MD Anderson and Zambia Virtual Clinical Research Training Program consisted of weekly virtual lectures and support of Zambian-led research protocols through longitudinal mentorship groups that included CDH faculty and MDA peer and faculty mentors. Participants were contacted via email to take part in semi-structured interviews, which were conducted via teleconference and audio-recorded, transcribed, and coded. Emergent themes were extracted and are presented with representative verbatim quotations. RESULTS: Thirteen of the 14 (93%) trainees were interviewed. Emergent themes included (1) participants having diverse educational backgrounds but limited exposure to clinical research, (2) importance of cancer research specific to a resource-constrained setting, (3) complementary roles of peer mentors and local and international faculty mentors, (4) positive impact on clinical research skills but importance of a longitudinal program and early exposure to clinical research, and (5) challenges with executing research protocols. CONCLUSION: To our knowledge, this is the first qualitative study of African clinical oncology trainees participating in a virtual clinical research training program. The lessons learned from semi-structured interviews with participants in MOZART provided valuable insights that can inform the development of similar clinical research training efforts and scale-up.

Metagenomes of rectal swabs in larger, advanced stage cervical cancers have enhanced mucus degrading functionalities and distinct taxonomic structure.

BACKGROUND: Gut microbiome community composition differs between cervical cancer (CC) patients and healthy controls, and increased gut diversity is associated with improved outcomes after treatment. We proposed that functions of specific microbial species adjoining the mucus layer may directly impact the biology of CC. METHOD: Metagenomes of rectal swabs in 41 CC patients were examined by whole-genome shotgun sequencing to link taxonomic structures, molecular functions, and metabolic pathway to patient's clinical characteristics. RESULTS: Significant association of molecular functions encoded by the metagenomes was found with initial tumor size and stage. Profiling of the molecular function abundances and their distributions identified 2 microbial communities co-existing in each metagenome but having distinct metabolism and taxonomic structures. Community A (Clostridia and Proteobacteria predominant) was characterized by high activity of pathways involved in stress response, mucus glycan degradation and utilization of degradation byproducts. This community was prevalent in patients with larger, advanced stage tumors. Conversely, community B (Bacteroidia predominant) was characterized by fast growth, active oxidative phosphorylation, and production of vitamins. This community was prevalent in patients with smaller, early-stage tumors. CONCLUSIONS: In this study, enrichment of mucus degrading microbial communities in rectal metagenomes of CC patients was associated with larger, more advanced stage tumors.

Impact of treatment modality on pelvic floor dysfunction among uterine cancer survivors.

OBJECTIVE: Pelvic floor dysfunction is a common adverse effect of uterine cancer treatment. In this study we compared patient-reported outcomes regarding pelvic floor dysfunction among uterine cancer survivors after hysterectomy and bilateral salpingo-oophorectomy, surgery and brachytherapy, or surgery and external beam radiotherapy with or without brachytherapy versus women who had a hysterectomy for benign indications. METHODS: We used the validated 20-item Pelvic Floor Distress Inventory to assess lower urinary distress, colorectal distress, and pelvic organ prolapse dysfunction in each treatment group. Pelvic floor dysfunction-related quality of life in these domains was compared across treatment modalities using the Pelvic Floor Impact Questionnaire-7. Treatment type, body mass index, comorbidities, and number of vaginal births were obtained from medical records. A zero-inflated negative binomial regression model was used to assess the association of treatment regimens and covariates relative to the non-cancer cohort. RESULTS: A total of 309 surveys were analyzed. The median age of the patients at surgery was 58 years (range 20-87) and the median age at survey completion was 66 years (range 34-92). Most participants reported experiencing at least one symptom of pelvic floor dysfunction (76% by Pelvic Floor Distress Inventory-2). The type of treatment had no effect on overall pelvic floor dysfunction on multivariate analysis (all p>0.05). Worse urinary-related symptoms were associated with higher body mass index at surgery (OR 1.41), higher age at time of survey (OR 1.07), and higher numbers of vaginal births (OR 1.43) (all p<0.05). CONCLUSIONS: Overall, pelvic floor dysfunction did not significantly vary by treatment modality. Our findings suggest complex interactions among age, body mass index, and parity as to how uterine cancer treatment affects pelvic floor quality of life, which should be considered in the choice of treatment strategy and patient counseling.

Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer.

BACKGROUND: Nelfinavir (NFV), an HIV-1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer. METHODS: Two dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse-phase-protein-array analyses. RESULTS: NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose-limiting toxicity, whereas no dose-limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow-up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT. CONCLUSIONS: NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.

The association between protease inhibitors and anal cancer outcomes in veterans living with HIV treated with definitive chemoradiation: a retrospective study.

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing, particularly in people living with HIV (PLWH). There is concern that radiosensitizing drugs, such as protease inhibitors, commonly used in the management of HIV, may increase toxicities in patients undergoing chemoradiation. This study examines treatment outcomes and toxicities in PLWH managed with and without protease inhibitors who are receiving chemoradiation for anal cancer. METHODS: Patient demographic, HIV management, and cancer treatment information were extracted from multiple Veterans Affairs databases. Patients were also manually chart reviewed. Among PLWH undergoing chemoradiation for anal carcinoma, therapy outcomes and toxicities were compared between those treated with and without protease inhibitors at time of cancer treatment. Statistical analysis was performed using chi-square, Cox regression analysis, and logistic regression. RESULTS: A total of 219 PLWH taking anti-retroviral therapy undergoing chemoradiation for anal cancer were identified and included in the final analysis. The use of protease inhibitors was not associated with any survival outcome including colostomy-free survival, progression-free survival, or overall survival (all adjusted hazard ratio p-values> 0.05). Regarding toxicity, protease inhibitor use was not associated with an increased odds of hospitalizations or non-hematologic toxicities; however, protease inhibitor use was associated with increased hospitalizations for hematologic toxicities, including febrile neutropenia (p < 0.01). CONCLUSION: The use of protease inhibitors during chemoradiation for anal carcinoma was not associated with any clinical outcome or increase in non-hematologic toxicity. Their use was associated with increased hospitalizations for hematologic toxicities. Further prospective research is needed to evaluate the safety and efficacy of protease inhibitors for patients undergoing chemoradiation.

Lymphadenectomy is associated with an increased risk of postoperative venous thromboembolism in early stage endometrial cancer.

OBJECTIVES: In patients undergoing surgery for early stage endometrial cancer, we sought to evaluate the effect of lymphadenectomy (LND), as well as surgical route, on the risk of postoperative venous thromboembolism (VTE). METHODS: The Surveillance, Epidemiology, and End Results cancer registries (2000-2013) linked to Medicare claims follow up from 1999 to 2014 was accessed to identify those with stage I-II endometrioid endometrial cancer who underwent hysterectomy. Performance of LND, 90-day incidence of postoperative VTE, open vs minimally invasive surgery (MIS), demographics, comorbidities, grade, and stage were collected. A washout period of 12 months with no prior VTE was required. t-test, Chi square test, univariate and multivariable Poisson regression with robust variance estimator were used. RESULTS: A total of 15,101 patients had hysterectomy for early stage endometrial cancer. LND was performed in 9004 (60%) patients. VTE was found in 486 patients. There were 346 VTEs (3.8%) in the LND group vs 140 (2.3%) in those without LND (RR = 1.67, p < 0.0001). Adjusting for age, stage, grade, comorbidities and surgical approach, LND remained a significant risk for VTE (RR = 1.7, p < 0.001). In those who underwent MIS, LND was associated with a two-fold increase in the risk of VTE (p = 0.0008) (adjusted RR = 1.99, p = 0.0014) and had a statistically comparable rate of VTE when compared to the open surgical approach (p = 0.054). CONCLUSIONS: LND is associated with an increased 90-day risk of postoperative VTE in patients undergoing surgery for early stage endometrial cancer. The need for extended postoperative VTE prophylaxis in patients undergoing LND via MIS needs further exploration.

Immunotherapy combined with high- and low-dose radiation to all sites leads to complete clearance of disease in a patient with metastatic vaginal melanoma.

A 73-year-old woman with metastatic vaginal mucosal melanoma that had progressed on ipilimumab and nivolumab experienced clinical and radiographic complete response to dual checkpoint inhibitor immunotherapy given in combination with high-dose plus low-dose radiation. General characteristics and treatment options in this disease are highlighted.

Utilization and survival outcomes of sequential, concurrent and sandwich therapies for advanced stage endometrial cancers by histology.

OBJECTIVE: To determine the impact on overall survival (OS) of different modalities of adjuvant therapy for the treatment of stage III endometrial cancer (EC), by histology. METHODS: Stage 3 endometrioid (EAC), serous (SER), clear cell (CC), and carcinosarcoma (CS) patients who underwent primary surgical staging from 2000 to 2013 were identified in SEER-Medicare. Adjuvant therapy was defined by a 4-arm comparator grouping (none; RT only; CT only; combination RT), as well as by an 8-arm comparator grouping (none; RT only; CT only; concurrent CT-RT; concurrent CT-RT then CT; Serial CT-RT; serial RT-CT; sandwich). Modality of RT and CT were analyzed using Kaplan-Meier estimates, log rank tests, and multivariable cox modeling. RESULTS: Of 2870 cases identified (1798 EAC, 606 SER, 118 CC, 348 CS), 31.5% received no adjuvant therapy. The remainder received RT or CT alone, concurrent RT-CT, serial or sandwich modalities. OS differed by adjuvant therapy in adjusted and unadjusted models, when combining all histologies, and when stratifying by histology using both the 4-arm, and 8-arm comparator analyses (log rank p < .05, all). By histology, in adjusted analyses, sandwich modality had the greatest improvement in OS for endometrioid, but pairwise comparisons did not identify a superior chemotherapy-based regimen. For serous and clear cell, the greatest improvement in OS was seen with concurrent RT-CT, and for carcinosarcoma, CT alone. CONCLUSIONS: OS for advanced EC significantly differs by histology and mode of adjuvant therapy. Future studies should evaluate the efficacy of combination-based adjuvant therapy versus chemotherapy alone, by histologic subtype and molecular signature.

Combining novel agents with radiotherapy for gynecologic malignancies: beyond the era of cisplatin.

Therapeutic strategies combining radiation therapy with novel agents have become an area of intense research focus in oncology and are actively being investigated for a wide range of solid tumors. The mechanism of action of these systemic agents can be stratified into three general categories: (1) enhancement or alteration of the immune system; (2) disruption of DNA damage response mechanisms; and (3) impediment of cellular signaling pathways involving growth, angiogenesis, and hypoxia. Pre-clinical data suggest that radiation therapy has immunogenic qualities and may optimize response to immuno-oncology therapies by priming the immune system, whereas other novel systemic agents can enhance radiosensitivity through augmentation of genomic instability and alteration of central signaling pathways related to growth and survival. Gynecologic cancers in particular have the potential for synergistic response to combination approaches incorporating radiation therapy and novel systemic therapies. Several clinical trials have been proposed to elucidate the efficacy and safety of such approaches. Here we discuss the mechanisms of novel therapies and the rationale for these combination strategies, reviewing the relevant pre-clinical and clinical data. We explore their optimal use with respect to indications, interactions, and potential synergy in combination with radiation therapy and review ongoing trials and active areas of investigation.

HIV infection is not associated with the initiation of curative treatment in women with cervical cancer in Botswana.

BACKGROUND: Cervical cancer is the leading cause of cancer death in Sub-Saharan Africa. The risk of developing cancer is increased for women living with human immunodeficiency virus (HIV) infection. It is unknown which factors predict the initiation of curative chemoradiotherapy (CRT) in resource-limited settings and whether HIV is associated with initiating curative CRT in settings with a high HIV burden. METHODS: All women living with and without HIV infection who were initiating curative and noncurative CRT for locally advanced cervical cancer in Botswana were prospectively enrolled in an observational study. The factors associated with receiving CRT were evaluated in all patients and the subgroup of women living with HIV. RESULTS: Of 519 enrolled women, 284 (55%) initiated CRT with curative intent. The curative cohort included 200 women (70.4%) who were living with HIV and had a median CD4 count of 484.0 cells/µL (interquartile range, 342.0-611.0 cells/µL). In the noncurative cohort, 157 of 235 women (66.8%) were living with HIV and had a median CD4 count of 476.5 cells/µL (interquartile range, 308.0-649.5 cells/µL). HIV status was not associated with initiating curative CRT (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.58-1.56). The factors associated with receiving curative CRT treatment on multivariable analysis in all patients included baseline hemoglobin levels ≥10 g/dL (OR, 1.80; 95% CI, 1.18-2.74) and stage I or II versus stage III or IV disease (OR, 3.16; 95% CI, 2.10-4.75). Women aged >61 years were less likely to receive curative treatment (OR, 0.43; 95% CI, 0.24-0.75). Among women who were living with HIV, higher CD4 cell counts were associated with higher rates of CRT initiation. CONCLUSIONS: The initiation of CRT with curative intent does not depend on HIV status. Significant predictors of CRT initiation include baseline hemoglobin level, disease stage, and age.

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours.

BACKGROUND: We conducted a phase I trial evaluating pembrolizumab+hypofractionated radiotherapy (HFRT) for patients with metastatic cancers. METHODS: There were two strata (12 patients each): (i) NSCLC/melanoma progressing on prior anti-PD-1 therapy, (ii) other cancer types; anti-PD-1-naive. Patients received 6 cycles of pembrolizumab, starting 1 week before HFRT. Patients had ≥2 lesions; only one was irradiated (8 Gy × 3 for first half; 17 Gy × 1 for second half in each stratum) and the other(s) followed for response. RESULTS: Of the 24 patients, 20 (83%) had treatment-related adverse events (AEs) (all grade 1 or 2). There were eight grade 3 AEs, none treatment related. There were no dose-limiting toxicities or grade 4/5 AEs. Stratum 1: two patients (of 12) with progression on prior PD-1 blockade experienced prolonged responses (9.2 and 28.1 months). Stratum 2: one patient experienced a complete response and two had prolonged stable disease (7.4 and 7.0 months). Immune profiling demonstrated that anti-PD-1 therapy and radiation induced a consistent increase in the proliferation marker Ki67 in PD-1-expressing CD8 T cells. CONCLUSIONS: HFRT was well tolerated with pembrolizumab, and in some patients with metastatic NSCLC or melanoma, it reinvigorated a systemic response despite previous progression on anti-PD-1 therapy. CLINICAL TRIAL REGISTRATION: NCT02303990 ( www.clinicaltrials.gov ).

Evolving Paradigms in HIV Malignancies: Review of Ongoing Clinical Trials.

This review highlights current interventional clinical trials for HIV-associated malignancies (HIVAMs), with emphasis on 4 mechanistic areas: immunomodulatory therapies and gene therapies, including immune checkpoint inhibitors; cytotoxic therapies; novel tumor-targeted and virally targeted therapies in both AIDS-defining and non-AIDS-defining cancers (NADC); and other screening or topical/ablative interventions. A search on ClinicalTrials.gov located 35 trials, including 12 immunomodulatory or gene therapy trials, 6 cytotoxic therapy trials, 10 trials of therapies with tumor or viral molecular targets, and 7 trials evaluating screening interventions or topical or ablative therapies. Study drugs, mechanisms, and outcomes of interest, including future directions, are discussed. Targeted therapies and immunotherapies address not only the tumor but underlying viral oncogens, including possible benefits on HIV-specific immunologic control. The resulting science from the trials listed in this review will provide important translational breakthroughs for people living with HIV (PLWH) and cancer. We highlight disease-specific challenges that could be addressed in future studies, including testing the safety and efficacy of cutting-edge immunotherapy and targeted treatments used in the general cancer population, and improving gaps in knowledge and practice for cancer screening and its treatment, especially in low-resource regions. Additional important considerations include identification of novel therapies for virally mediated tumors that disproportionally present in PLWH, how to treat persons with HIVAM and advanced immunosuppression, and how to comanage both diseases in antiretroviral therapy-naïve persons and those receiving care in settings where supportive therapies for hematologic toxicities and infections are limited. Current and future clinical trials should address needs of both resource-replete and -limited regions, as well as cancers that are uncommon in or respond differently to HIV-negative populations (eg, Kaposi sarcoma or anal cancer), in addition to an increased focus on NADCs not traditionally linked with HIV, such as lung or gastrointestinal tumors.

Use of Aggressive Surveillance for Locoregional Endometrial Cancer After Local Therapy.

PURPOSE/OBJECTIVES: Current guidelines do not recommend routine surveillance imaging as part of follow-up care for patients treated for locoregional endometrial carcinoma. This study seeks to determine the potential benefit of routine surveillance imaging by evaluating outcomes of patients whose recurrences were detected on routine surveillance compared to those whose recurrences were identified after presenting with symptoms. MATERIALS/METHODS: We conducted a retrospective review of patients who developed recurrence after surgical treatment, with or without adjuvant therapy, for locoregional endometrial carcinoma. A total of 149 patients were identified with adequate clinical information regarding the recurrence. Cox proportional hazards regression analysis was used to estimate overall survival and progression-free survival. RESULTS: The median age of patients at diagnosis was 69.2 years (range, 38.0-99.5 years). Initial stages included stage I, 49.7%; stage II, 10.1%; stage III, 38.3%; and stage IV, 1.3%. Histologic diagnoses included endometrioid adenocarcinoma, 48.3%; and other diagnoses (including papillary serous carcinoma, clear cell carcinoma, and carcinosarcoma), 51.7%. Patients were initially treated with a variety of therapies: surgery alone in 20.8%, surgery and radiation in 25.5%, surgery and chemotherapy in 12.1%, and trimodality therapy in 41.6%. Sites of recurrence included 20.8% vaginal, 14.8% pelvic and 64.4% distant sites. Recurrences were detected asymptomatically in 86 patients (57.7%) and symptomatically in 63 patients (42.3%). Of those detected asymptomatically, 80.2% were detected by imaging. Overall, when comparing symptomatic versus asymptomatic recurrences, there was no difference in overall survival (hazard ratio, 1.24; 95% confidence interval, 0.84-1.83; P = 0.29) or progression-free survival (hazard ratio, 1.14; 95% confidence interval, 0.77-1.70; P = 0.52). CONCLUSIONS: Patients who develop asymptomatic recurrences of their endometrial carcinoma do not seem to have a better prognosis than those who present with symptomatic recurrences. Thus, these results do not support routine imaging surveillance for patients treated for locoregional endometrial carcinoma. Further prospective evaluation is needed.

Bag and loop small bowel contouring strategies differentially estimate small bowel dose for post-hysterectomy women receiving pencil beam scanning proton therapy.

Background Small bowel (SB) dose-volume relationships established during initial computed tomography (CT) simulations may change throughout therapy due to organ displacement and motion. We investigated the impact of organ motion on SB dose-volume histograms (DVHs) in women with gynecologic malignancies treated with pencil beam scanning (PBS) proton therapy and compared PBS SB DVHs to intensity-modulated radiation therapy (IMRT). Material and methods Post-hysterectomy patients (n = 11) treated for gynecologic cancers were enrolled on an image-guided proton therapy protocol involving CT simulation with full (CTF) and empty (CTE) bladders and weekly/biweekly on-treatment scans. IMRT plans were generated for comparative analysis. SB was contoured as bowel loops or bowel bag. Wilcoxon signed-rank tests were used for matched-pair comparisons of SB, bladder, and rectum dose-volumes between CT scans and between PBS and IMRT plans. Results In PBS loops analysis, on-treatment DVH was significantly higher than CTF for doses <45 Gy (p < 0.05), and not significantly different than CTE. Specifically, V15 for loops was higher on-treatment (median 240 cm(3)) compared to CTF (median 169 cm(3), p = 0.03). In PBS bag analysis, on-treatment DVH was not significantly different from CTF across all dose ranges. Bowel bag V45 was not significantly different between on-treatment (median 540 cm(3)) and CTF (median 499 cm(3), p = 0.53). Decreasing bladder volume was associated with increasing V15 for loops and V45 for bowel bag (p < 0.005, both). Comparing PBS and IMRT, PBS resulted in significantly lower DVHs at low dose regions (<38 Gy) and higher DVHs at high dose regions (42.5-45.5 Gy) in both loops and bag analysis. IMRT plans demonstrated higher on-treatment SB loop DVHs and only minimal differences in bowel bag DVHs compared to CTF. Conclusions SB DVHs were well estimated by CTF bowel bag and underestimated by CTF loops in the setting of inconsistent bladder filling. Verifying bladder filling prior to treatment or using CTE for planning may more conservatively estimate SB dose-volume relationships.

The Impact of Adjuvant Therapy on Survival and Recurrence Patterns in Women With Early-Stage Uterine Carcinosarcoma: A Multi-institutional Study.

OBJECTIVE: The aim of the study was to characterize the impact of adjuvant therapy on survival in women with stage I/II uterine carcinosarcoma after primary surgery. METHODS: We reviewed records of 118 consecutively treated women with 2009 International Federation of Gynecology and Obstetrics stage I/II uterine carcinosarcoma who underwent hysterectomy between 1990 and 2014 at 4 academic institutions. Patients were categorized by adjuvant treatment group into observation, chemotherapy only, radiation only, and combined chemotherapy and radiation. Survival analyses were conducted using Kaplan-Meier and Cox proportional hazards models. RESULTS: Median follow-up was 28 months (range, 1-244 months). Lymphadenectomy was performed in 94 patients (80%). Postoperative management included observation (n = 37 [31%]), chemotherapy alone (n = 19 [16%]), radiation therapy (RT) alone (n = 24 [20%]), and combined RT and chemotherapy (n = 38 [32%]). Radiation therapy modality included vaginal brachytherapy in 22 patients, pelvic external beam RT in 21 patients, and combination in 19 patients. In 58% of women, chemotherapy consisted of carboplatin/paclitaxel. Median overall survival for all women was 97 months. On univariate analysis, adjuvant treatment group was associated with improved overall survival (hazard ratio [HR], 0.74; confidence interval [CI], 0.58-0.96; p = 0.02), freedom from vaginal recurrence (HR, 0.55; CI, 0.37-0.82]; p = 0.004), and freedom from any recurrence (HR, 0.70; CI, 0.54-0.92; p = 0.01). Pairwise comparisons demonstrated a significant benefit to chemoradiation over other adjuvant treatments. Adjuvant treatment group remained a significant covariate for all 3 end points on multivariate analysis as well. In addition, lymphadenectomy improved overall survival on multivariate analysis (HR, 0.24; CI, 0.09-0.61; p = 0.003). Of patients under observation only who had a recurrence, 8 (44%) of 18 had a recurrence in the vagina as the sole site of recurrence. By contrast, of women who received vaginal brachytherapy, significantly fewer had a recurrence in the vagina (1/42 [2.3%]; p < 0.003, log-rank test). CONCLUSIONS: In women with early-stage uterine carcinosarcoma, our data suggest superior survival end points with combined RT and chemotherapy. The frequency of vaginal recurrence suggests a role for incorporating vaginal brachytherapy in the adjuvant management of this disease.

Proton beam versus photon beam dose to the heart and left anterior descending artery for left-sided breast cancer.

PURPOSE: The purpose of this study was to compare the dose to heart, left anterior descending (LAD) artery and lung between proton and photon beam irradiation for left-sided early stage breast cancer. MATERIAL AND METHODS: Ten women with early stage left-sided breast cancer were treated with breast conserving surgery and radiation. Whole breast radiation was delivered for actual treatment via a tangential technique with deep inspiration breath hold (DIBH) utilizing inverse planned intensity-modulated radiation therapy (IMRT). Each patient was replanned on an Institutional Review Board (IRB)-approved prospective study using en face proton beam radiation with both uniform scanning (US) and pencil beam scanning (PBS) techniques. RESULTS: Both PBS (0.011 Gy) and US (0.009 Gy) proton plans resulted in a significantly lower mean heart dose compared to IMRT (1.612 Gy) (p < 0.05 for PBS vs. IMRT and US vs. IMRT). The Dmean, Dmin, Dmax, and D0.2cm(3) of the LAD with either proton technique were significantly lower (p = 0.005) compared to IMRT. Both US and PBS reduced the mean dose to the lungs compared to IMRT. The coverage of the breast planning target volume was comparable between photon and proton plans. CONCLUSIONS: The dose to whole heart was relatively low in this study of patients treated under conditions of DIBH. However, proton beam radiation was associated with lower minimum, maximum, and dose to 0.2 cm(3) of the LAD, which is the critical structure for late radiation therapy effects, compared to even the most optimized photon beam plan with DIBH and IMRT.

Physical activity, daily walking, and lower limb lymphedema associate with physical function among uterine cancer survivors.

PURPOSE: We sought to quantify the proportion of uterine cancer survivors who self-report poor physical function. We then sought to quantify the association of poor physical function with physical activity (PA), walking, and lower limb lymphedema (LLL), among women with a history of uterine cancer. METHODS: Physical function was quantified using the Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12) questionnaire. PA, walking, and LLL were measured using self-report questionnaire. PA was calculated using metabolic equivalent hours per week (MET-h week(-1)), and walking was calculated using blocks per day (blocks day(-1)). Logistic regression estimated odds ratios (OR) and 95 % confidence intervals (95 % CI). RESULTS: Among the 213 uterine cancer survivors in our survey (43 % response rate), 35 % self-reported poor physical function. Compared to participants who reported <3.0 MET-h week(-1) of PA, participants who reported ≥18.0 MET-h week(-1) of PA were less likely to have poor physical function (OR 0.03, 95 % CI 0.01-0.10; P trend < 0.0001). Compared to participants who reported <4.0 blocks day(-1) of walking, participants who reported ≥12.0 blocks day(-1) of walking were less likely to have poor physical function (OR 0.07, 95 % CI 0.03-0.19; P trend < 0.0001). Compared to participants who did not have LLL, participants with LLL were more likely to have poor physical function (OR 5.25, 95 % CI 2.41-11.41; P < 0.0001). CONCLUSION: Higher levels of PA and walking associate with a lower likelihood of reporting poor physical function. The presence of LLL associates with a higher likelihood of reporting poor physical function. These findings are hypothesis-generating and should be evaluated in future prospective studies.