Sexually transmitted infections and depot medroxyprogesterone acetate do not impact protection from simian HIV acquisition by long-acting cabotegravir in macaques.

OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STIs) that are known to increase HIV susceptibility in women. DESIGN: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. METHODS: The first study (n = 11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis and Trichomonas vaginalis. Six animals were CAB-LA treated and five were controls. The second study (n = 9) included a triple STI model with repeated exposures to C. trachomatis, T. vaginalis and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared with untreated controls over time. RESULTS: All six CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges, while the untreated animals became SHIV-infected after a median of two challenges (log-rank P < 0.001) or one challenge (log-rank P = 0.002), respectively. Both models recapitulated human STI disease, with vaginal discharge, ulcers, and seroconversion. CONCLUSION: In these high and sustained susceptibility models spanning more than 3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the CAB-LA dose used in clinical trials, and suggesting its insensitivity to multiple STIs and DMPA.

Preliminary toxicity results using partial breast 3D-CRT with once daily hypo-fractionation and deep inspiratory breath hold.

BACKGROUND: To evaluate the clinical outcomes of patients treated with 3D conformal Hypo-fractionated, deep Inspiratory breath-hold (DIBH), Partial breast radiotherapy, termed "HIP." HIP was implemented to merge the schedule of once-daily breast hypofractionation with partial breast treatment. METHODS: We identified 38 breast cancers in 37 patients from 2013 to 2014 treated at our institution with HIP following lumpectomy for early stage breast cancer. Patients received a hypo-fractionated course (≤ 20 fractions) of once daily radiation to the partial breast (lumpectomy cavity + margin) utilizing DIBH regardless of laterality. Clinical and treatment-related characteristics were obtained, including target volume and organ at risk (OAR) dosimetric characteristics. Patients were followed clinically and with at least yearly mammograms for up to 36 months (range 5-36 months). Acute and late toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. RESULTS: Patients received a median dose of 42.56 Gy in 16 Fractions (Fx) (range 40.05-53.2 Gy; and 15-20 Fx). OAR doses were low, with a mean heart dose of 0.37 Gy, an ipsilateral lung V20 mean of 4%, and a contralateral lung V5 of 1%. Acute toxicity (≤ grade 2) was present in 79% (n = 30) of the cases, with dermatitis being the most common finding (63%). Late grade 1-2 toxicity was present in 42% (n = 16) of the cases, with hyperpigmentation being the most common finding (n = 9). There were no severe acute or late toxicities (≥ grade 3). At a median follow up of 21 months, there were no local, regional, or distant failures. CONCLUSIONS: We report limited toxicity in this low risk cohort of patients with early stage breast cancer treated with HIP, a unique and logical combination of 3-D conformal external beam radiotherapy, moderate hypo-fractionation, and DIBH.

Techniques for intraoperative radiation therapy for early-stage breast carcinoma.

Intraoperative radiation therapy (IORT) is a method of accelerated partial breast irradiation developed to replace other longer courses of radiotherapy with a single radiation session administered at the time of breast-conserving surgery. The purpose of this review is to summarize the advantages and disadvantages of breast IORT techniques that are currently available, as well to consider potential alternative techniques for breast IORT or ultra-short course breast radiotherapy. Furthermore, we highlight the published outcomes for the IORT treatment approaches including: electron therapy, superficial photon therapy and other techniques. Potential future directions of IORT are explored including novel IORT techniques utilizing intraoperative brachytherapy with in-room imaging and rapid treatment planning.

Accelerated fraction radiotherapy with capecitabine as neoadjuvant therapy for borderline resectable pancreatic cancer.

BACKGROUND: A standard neoadjuvant regimen has not been defined for borderline resectable (BR) pancreatic cancer. This phase II trial was designed to determine the safety of accelerated fraction radiotherapy (AFRT) with capecitabine in patients with BR pancreatic cancer. METHODS: The patients had newly diagnosed BR adenocarcinoma of the pancreas and normal organ function. Intensity-modulated (n = 11) or 3D conformal (n = 2) radiotherapy was given to a dose of 50 Gy in 2.5-Gy fractions with capecitabine 825 mg/m(2) twice on radiation days. The primary outcome was the frequency of severe treatment-related adverse events (AEs). The study was stopped before planned interim analysis because of 2 severe (grades 4 and 5) gastric ulcerations. RESULTS: Thirteen patients were enrolled with a median age of 66 years. All patients completed treatment. Seven (54%) experienced grade 3+ treatment-related AEs. Severe gastric ulceration occurred in 2 patients despite receipt of ≥43 Gy to only 1% (2-3 cm(3)) of the stomach. Lymphopenia (n = 7) was the only other severe AE that occurred in >1 patient. In 7 of the 13 patients, disease had progressed outside the pancreas at restaging. Five of the 13 underwent resection, and all had >10% viable tumor. Median progression-free survival (PFS) was 2.4 months (95% CI 1.9-5.9), and median survival was 9.1 months (95% CI 5.9-not reached). Among those who underwent resection, median PFS was 13.0 months (95% CI 4.4-not reached). Median survival was not reached. CONCLUSIONS: Given the limited efficacy signal and severe gastric ulcerations, we do not recommend this regimen for pancreatic cancer. We also do not recommend the use of high doses per fraction outside a clinical trial.

A comparative analysis of 3D conformal deep inspiratory-breath hold and free-breathing intensity-modulated radiation therapy for left-sided breast cancer.

Patients undergoing radiation for left-sided breast cancer have increased rates of coronary artery disease. Free-breathing intensity-modulated radiation therapy (FB-IMRT) and 3-dimensional conformal deep inspiratory-breath hold (3D-DIBH) reduce cardiac irradiation. The purpose of this study is to compare the dose to organs at risk in FB-IMRT vs 3D-DIBH for patients with left-sided breast cancer. Ten patients with left-sided breast cancer had 2 computed tomography scans: free breathing and voluntary DIBH. Optimization of the IMRT plan was performed on the free-breathing scan using 6 noncoplanar tangential beams. The 3D-DIBH plan was optimized on the DIBH scan and used standard tangents. Mean volumes of the heart, the left anterior descending coronary artery (LAD), the total lung, and the right breast receiving 5% to 95% (5% increments) of the prescription dose were calculated. Mean volumes of the heart and the LAD were lower (p<0.05) in 3D-DIBH for volumes receiving 5% to 80% of the prescription dose for the heart and 5% for the LAD. Mean dose to the LAD and heart were lower in 3D-DIBH (p≤0.01). Mean volumes of the total lung were lower in FB-IMRT for dose levels 20% to 75% (p<0.05), but mean dose was not different. Mean volumes of the right breast were not different for any dose; however, mean dose was lower for 3D-DIBH (p = 0.04). 3D-DIBH is an alternative approach to FB-IMRT that provides a clinically equivalent treatment for patients with left-sided breast cancer while sparing organs at risk with increased ease of implementation.

A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients.

BACKGROUND: We tested if magnesium would diminish bothersome hot flashes in breast cancer patients. METHODS: Breast cancer patients with at least 14 hot flashes a week received magnesium oxide 400 mg for 4 weeks, escalating to 800 mg if needed. Hot flash score (frequency × severity) at baseline was compared to the end of treatment. RESULTS: Of 29 who enrolled, 25 women completed treatment. The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 (standard error (SE), 13.7) to 27.7 (SE, 5.7), a 41.4% reduction, p = 0.02, two-sided paired t test. Hot flash score was reduced from 109.8 (SE, 40.9) to 47.8 (SE, 13.8), a 50.4% reduction, p = 0.04. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial. CONCLUSIONS: Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal. A randomized placebo-controlled trial is planned.

Tumor bed boost omission after negative re-excision in breast-conservation treatment.

BACKGROUND: We evaluated the necessity of a tumor bed boost after whole-breast radiotherapy for early-stage breast cancer after breast-conserving surgery and negative re-excision. METHODS: Of patients treated at the Virginia Commonwealth and Tufts Universities with breast-conservation therapy for early-stage breast cancer between 1983 and 1999, 205 required re-excision of the tumor cavity to obtain clear margins and were found to be without residual disease. Adjuvant conventionally fractionated whole-breast radiotherapy was given to a total dose of 50 Gy in 25 fractions. The tumor bed boost was omitted. RESULTS: The median follow-up was 98 months (range, 6-229 months). The tumor histological diagnosis was primarily infiltrating ductal carcinoma (183 cases; 89%). Nodal involvement was documented in 49 cases (24%). There were four documented recurrences at the tumor bed site. Five in-breast recurrences were documented to be in a location removed from the tumor bed. The overall Kaplan-Meier 15-year in-breast control rate was 92.4%, and the freedom from true recurrence rate was 97.6%. CONCLUSIONS: The findings support the concept that postlumpectomy radiotherapy can be tailored according to the degree of surgical resection. There is an easily identifiable subgroup of patients who can avoid a tumor bed boost, thus resulting in a reduced treatment time and improved cosmesis, while maintaining local control rates that approach 100%. The data suggest that in patients who undergo a negative re-excision, treatment with whole-breast radiotherapy to 50 Gy is a sufficient dose to maximally reduce the risk of local recurrence.

Breast cancer: new radiation treatment options.

Conventional radiotherapeutic treatment for early and advanced breast cancer has been based on broad-field radiation treatment principles that date back several decades. Although these strategies have been successful, newer techniques now offer the ability to incorporate improved target imaging, dosimetric planning, and treatment delivery into the treatment design. These newer techniques include accelerated partial-breast irradiation and hypofractionated whole-breast irradiation for early-stage breast cancer, and intensity-modulated radiotherapy (IMRT) for both early and advanced breast cancer. Accelerated partial-breast irradiation and hypofractionated whole-breast radiotherapy are treatment approaches that promise both reduced overall treatment times and the potential for increased use of breast-conservation therapy. IMRT offers unparalleled dose homogeneity and conformality that enables dose reduction to normal structures with the potential to reduce treatment toxicity and improve cosmesis. Based on the published literature, an increasing number of treatment facilities are offering treatment with these techniques. However, further clinical study remains important to thoroughly define the appropriate clinical setting, patient selection criteria, and limitations for each of these innovative treatment approaches.

Accelerated superfractionated radiotherapy with concomitant boost for locally advanced head-and-neck squamous cell carcinomas.

PURPOSE: A growing body of evidence supports the efficacy of accelerated superfractionated radiotherapy with concomitant boost for advanced head-and-neck carcinomas. This study represents a single-institution experience, performed to identify the factors influencing tumor control, survival, and toxicity. MATERIALS AND METHODS: Between 1988 and 1999, 133 patients with primary squamous cell head-and-neck carcinoma underwent accelerated superfractionated radiotherapy using a concomitant boost. The concomitant boost in this regimen was delivered using reduced fields delivered 3 times weekly in a twice-daily schedule during the final phase. The total radiation dose ranged from 64.8 Gy to 76.5 Gy (mean 71.1). Patients were evaluated in follow-up for local control and late toxicity. Multivariate analysis of treatment and patient parameters was performed to evaluate their influence on toxicity, local control, and overall survival. RESULTS: With a mean follow-up of 37 months, the actuarial overall survival rate for the entire group at 5 years was 24% and the local control rate was 57%. The tumor volume was the most significant predictor of local control, such that each 1-cm(3) increase in volume was associated with a 1% decrease in local control. For patients with tumor volumes 30 cm(3), the 5-year disease-specific survival rate was 52% and 27% (p = 0.004) and locoregional control rate was 76% and 26% (p <0.001), respectively. Seventy-six patients with a minimum of 12 months and median of 39 months toxicity follow-up were studied for late effects. None of these patients experienced Grade 4 or 5 toxicity. The actuarial rate of significant toxicity (Grade III or greater) was 32% at 5 years. Of the toxicities observed, xerostomia (19%) was the most common. Multivariate analysis revealed N stage and dose as independent predictors of Grade 3 effects. CONCLUSION: The locoregional control and survival for patients in this institutional experience compare favorably to other published reports. Tumors of the larynx had the best prognosis. Larger volume tumors were associated with significantly lower local control and survival. Significant late effects were related to dose and nodal status.