Lilie L. Lin

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

BackgroundNelfinavir (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.MethodsTwo 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.ResultsNFV 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.ConclusionsNFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.

Gut microbiome diversity is an independent predictor of survival in cervical cancer patients receiving chemoradiation

AbstractDiversity of the gut microbiome is associated with higher response rates for cancer patients receiving immunotherapy but has not been investigated in patients receiving radiation therapy. Additionally, current studies investigating the gut microbiome and outcomes in cancer patients may not have adjusted for established risk factors. Here, we sought to determine if diversity and composition of the gut microbiome was independently associated with survival in cervical cancer patients receiving chemoradiation. Our study demonstrates that the diversity of gut microbiota is associated with a favorable response to chemoradiation. Additionally, compositional variation among patients correlated with short term and long-term survival. Short term survivor fecal samples were significantly enriched in Porphyromonas, Porphyromonadaceae, and Dialister, whereas long term survivor samples were significantly enriched in Escherichia Shigella, Enterobacteriaceae, and Enterobacteriales. Moreover, analysis of immune cells from cervical tumor brush samples by flow cytometry revealed that patients with a high microbiome diversity had increased tumor infiltration of CD4+ lymphocytes as well as activated subsets of CD4 cells expressing ki67+ and CD69+ over the course of radiation therapy. Modulation of the gut microbiota before chemoradiation might provide an alternative way to enhance treatment efficacy and improve treatment outcomes in cervical cancer patients.

Quality Assurance in Clinical Trials Requiring Radiation Therapy in Sub-Saharan Africa

Given the increasing availability of radiation therapy in sub-Saharan Africa, clinical trials that include radiation therapy are likely to grow. Ensuring appropriate delivery of radiation therapy through rigorous quality assurance is an important component of clinical trial execution. We reviewed the process for credentialing radiation therapy sites and radiation therapy quality assurance through the Imaging and Radiation Oncology Core (IROC) Houston Quality Assurance Center for AIDS Malignancy Consortium (AMC)-081, a multicenter study of cisplatin and radiation therapy for women with locally advanced cervical cancer living with HIV, conducted by the AIDS Malignancy Consortium at 2 sites in South Africa and Zimbabwe. Women living with HIV with newly diagnosed stage IB2, IIA (>4 cm), IIB-IVA cervical carcinoma (per the 2009 International Federation of Gynecology and Obstetrics [FIGO] staging classifications) were enrolled in AMC-081. They received 3-dimensional conformal external beam radiation therapy (EBRT) to the pelvis (41.4-45 Gy) using a linear accelerator, high-dose-rate brachytherapy (6-9 Gy to point A with each fraction and up to 4 fractions), and concurrent weekly cisplatin (40 mg/m All of the 38 women enrolled in AMC-081 received ±5% of the protocol-specified prescribed dose of EBRT. Geometry of brachytherapy applicator placement was scored as per protocol in all implants. Doses to points A and B, International Commission on Radiation Units and Measurements (ICRU) bladder, or ICRU rectum required correction by IROC in >50% of the implants. In the final evaluation, 58% of participants (n = 22) were treated per protocol, 40% (n = 15) had minor protocol deviations, and 3% (n = 1) had major protocol deviations. No records were received within 60 days of treatment completion as requested in the protocol. Major radiation therapy deviations were low, but timely submission of radiation therapy data did not occur. Future studies, especially those that include specialized radiation therapy techniques such as stereotactic or intensity-modulated radiation therapy, will require pathways to ensure timely and adequate quality assurance.

Improving Access to Radiation Therapy Globally To Meet World Health Organization Goals To Eliminate Cervical Cancer

Cervical cancer treatment outcomes and survival in Botswana by human immunodeficiency virus status: Ipabalele study results

Abstract Background Cervical cancer is a leading morbidity/mortality cause, frequently co-occurring with human immunodeficiency virus (HIV) positivity, in Botswana. We examined long-term outcomes for Ipabalele study participants receiving curative chemoradiation for locally advanced cervical cancer (2015-2019) by HIV status. Methods Clinical and outcome data were collected at baseline, treatment completion, and 3 months thereafter. Patients were followed for up to 5 years. Overall survival (OS) was evaluated using Kaplan-Meier curves and Cox regression. Results The cohort comprised 295 patients (73.8% with HIV, younger at diagnosis [P < .001]) followed for a median of 44.2 months. Complete response was seen in 217/278 (76.1%) patients. Two- and 5-year OS rates were 73.4% and 59.9%, respectively, with no difference by HIV status. OS was associated negatively with advanced disease stage (III: hazard ratio [HR] 13.23, P < .001; IV: HR 7.8, P = .008) and positively with increased radiation (HR 0.977, P = .0005) and chemotherapy (HR 0.85, P = .005). Clinical response was associated negatively with advanced disease (IV: HR 0.113, P = .002) and positively with increased radiation (P = .009). Toxicity did not differ by HIV status. The most common grade-≥-2 non-hematological and hematological toxicities were radiation dermatitis (39.8%) and reduced white blood cell count (66.05%), respectively. Conclusions In this cervical cancer cohort with good HIV status control, treatment outcomes and OS were associated with disease and treatment factors, not the HIV status. Early screening and education regarding treatment protocols are crucial to improve cervical cancer outcomes in Botswana.

Human Papilloma Virus Circulating Cell-Free DNA Kinetics in Patients with Cervical Cancer Undergoing Definitive Chemoradiation

Abstract Purpose: Human papillomavirus (HPV) is a significant cause of cervical cancer. We hypothesized that detecting viral cell-free HPV DNA (cfDNA) before, during, and after chemoradiation (chemoRT) could provide insights into disease extent, clinical staging, and treatment response. Experimental Design: A total of 66 patients with locally advanced cervical cancer were enrolled between 2017 and 2023, with 49 receiving standard-of-care treatment and 17 participating in a clinical trial combining a therapeutic HPV vaccine (PDS0101; IMMUNOCERV). Plasma was collected at baseline, weeks 1, 3, and 5 of chemoRT, and 3 to 4 months after chemoRT. HPV cfDNA was quantified using droplet digital PCR targeting the HPV E6/E7 oncogenes of 13 high-risk types. MRI was performed at baseline and before brachytherapy. Results: The median follow-up was 23 months, with recurrence-free survival (RFS) of 78.4% at 2 years. Baseline nodal disease extent correlated with HPV cfDNA levels. HPV cfDNA levels peaked in week 1 of radiation and decreased through treatment. Patients receiving the PDS0101 vaccine had a higher rate of undetectable HPV type 16 cfDNA compared with those who received standard-of-care therapy. HPV cfDNA clearance correlated with better 2-year RFS (92.9% vs. 30%, log-rank; P = 0.0067). The strongest predictor of RFS was HPV cfDNA clearance in follow-up achieving a concordance index score of 0.83, which improved when combined with MRI response (concordance index, 0.88). Conclusions: HPV cfDNA levels change dynamically during chemoRT. HPV cfDNA levels at follow-up predict RFS, and delivery of therapeutic HPV vaccine with chemoRT was linked to rapid HPV cfDNA decline. Monitoring HPV cfDNA during and after chemoRT may guide tailoring of personalized treatment.