Melody J. Xu

A Systematic Review of Radiotherapy Capacity in Low- and Middle-Income Countries

Objectives: The cancer burden in low- and middle-income countries (LMIC) is substantial. The purpose of this study was to identify and describe country and region-specific patterns of radiotherapy (RT) facilities in LMIC. Methods: A systematic review of the literature was undertaken. A search strategy was developed to include articles on radiation capacity in LMIC from the following databases: PubMed, Embase, CINAHL Plus, Global Health, and the Latin American and Caribbean System on Health Sciences Information. Searches included all literature up to April 2013. Results: A total of 49 articles were included in the review. Studies reviewed were divided into one of four regions: Africa, Asia, Eastern Europe, and South America. The African continent has the least amount of resources for RT. Furthermore, a wide disparity exists, as 60% of all machines on the continent are concentrated in Egypt and South Africa while 29 countries in Africa are still lacking any RT resource. A significant heterogeneity also exists across Southeast Asia despite a threefold increase in megavoltage teletherapy machines from 1976 to 1999, which corresponds with a rise in economic status. In LMIC of the Americas, only Uruguay met the International Atomic Energy Agency recommendations of 4 MV/million population, whereas Bolivia and Venezuela had the most radiation oncologists (>1 per 1000 new cancer cases). The main concern with the review of RT resources in Eastern Europe was the lack of data. Conclusion: There is a dearth of publications on RT therapy infrastructure in LMIC. However, based on limited published data, availability of RT resources reflects the countries’ economic status. The challenges to delivering radiation in the discussed regions are multidimensional and include lack of physical resources, lack of human personnel, and lack of data. Furthermore, access to existing RT and affordability of care remains a large problem.

A Novel Approach for the Detection and Genetic Analysis of Live Melanoma Circulating Tumor Cells

Background Circulating tumor cell (CTC) detection and genetic analysis may complement currently available disease assessments in patients with melanoma to improve risk stratification and monitoring. We therefore sought to establish the feasibility of a telomerase-based assay for detecting and isolating live melanoma CTCs. Methods The telomerase-based CTC assay utilizes an adenoviral vector that, in the presence of elevated human telomerase activity, drives the amplification of green fluorescent protein. Tumor cells are then identified via an image processing system. The protocol was tested on melanoma cells in culture or spiked into control blood, and on samples from patients with metastatic melanoma. Genetic analysis of the isolated melanoma CTCs was then performed for BRAF mutation status. Results The adenoviral vector was effective for all melanoma cell lines tested with sensitivity of 88.7% (95%CI 85.6-90.4%) and specificity of 99.9% (95%CI 99.8-99.9%). In a pilot trial of patients with metastatic disease, CTCs were identified in 9 of 10 patients, with a mean of 6.0 CTCs/mL. At a cutoff of 1.1 CTCs/mL, the telomerase-based assay exhibits test performance of 90.0% sensitivity and 91.7% specificity. BRAF mutation analysis of melanoma cells isolated from culture or spiked control blood, or from pilot patient samples was found to match the known BRAF mutation status of the cell lines and primary tumors. Conclusions To our knowledge, this is the first report of a telomerase-based assay effective for detecting and isolating live melanoma CTCs. These promising findings support further studies, including towards integrating into the management of patients with melanoma receiving multimodality therapy.

Cervical cancer control in HIV-infected women: Past, present and future

Since the initial recognition of acquired immunodeficiency syndrome (AIDS) in 1981, an increased burden of cervical cancer was identified among human immunodeficiency virus (HIV)-positive women. Introduction of antiretroviral therapy (ART) decreased risks of opportunistic infections and improved overall survival. HIV-infected women are living longer. Introduction of the human papillomavirus (HPV) vaccine, cervical cancer screening and early diagnosis provide opportunities to reduce cervical cancer associated mortality. In line with 2030 Sustainable Development Goals to reduce mortality from non-communicable diseases, increased efforts need to focus on high burden countries within sub-Saharan Africa (SSA). Despite limitations of resources in SSA, opportunities exist to improve cancer control. This article reviews advancements in cervical cancer control in HIV-positive women.

Radiotherapeutic Management of Non–Small Cell Lung Cancer in the Minimal Resource Setting

ABSTRACT Lung cancer is the most common cancer worldwide and the fifth most common cause of death globally. Its incidence continues to increase, especially within low‐ and middle‐income countries (LMICs), which have limited capacity to address the growing need for treatment. The standard of care for lung cancer treatment often involves radiation therapy (RT), which plays an important therapeutic role in curative‐intent treatment of early‐stage to locally advanced disease, as well as in palliation. The infrastructure, equipment, and human resources required for RT may be limited in LMICs. However, this narrative review discusses the scope of the problem of lung cancer in LMICs, the role of RT technologies in lung cancer treatment, and RT capacity in developing countries. Strategies are presented for maximizing the availability and impact of RT in settings with minimal resource availability, and areas for potential future innovation are identified. Priorities for LMICs involve increasing access to RT equipment and trained health care professionals, ensuring quality of care, providing guidance on priority setting with limited resources, and encouraging innovation to increase the economic efficiency of RT delivery. Several international initiatives are currently under way and represent important first steps toward scaling up RT in LMICs to treat lung cancer.

Clinical trials in low and middle-income countries — Successes and challenges

Gynecologic malignancies affect women in low and middle-income countries (LMICs) at equal or higher rates compared to high income countries (HICs), yet practice guidelines based on clinical trials performed in HICs do not routinely account for resource disparities between these regions. There is a need and growing interest for executing clinical trials in LMICs. This has led to the creation of multinational cooperative groups and the initiation of several ongoing clinical trials in Mexico, China, and Korea. In this article we describe the challenges involved in initiating clinical trials in LMICs, review current efforts within surgical, medical, and radiation oncology, and introduce high priority topics for future research.

Survival Outcomes Improved in Contemporary Cohort of Patients With Pelvic or Abdominal Recurrence After Treatment for Stage I/ii Endometrial Carcinoma

Objectives: Pelvic and abdominal recurrences in stage I/II endometrial carcinoma are associated with poor outcomes, yet prognostic factors for survival after recurrence are not well described. Herein, we identify patients with pelvic or abdominal recurrence after surgery for stage I/II endometrial carcinoma and describe symptoms at presentation, prognostic factors, and salvage treatment toxicity. Materials and Methods: This is a retrospective cohort of 20 consecutively treated patients with recurrence after treatment for stage I/II endometrial carcinoma followed by our Institution’s Radiation Oncology Department from 1998 to 2015. Results: The median time to pelvic or abdominal recurrence was 18.1 months (range, 4.2 to 59.6 mo), with 50% of recurrences at extranodal locations. Two-year progression-free survival (PFS) was 44% and 2-year overall survival (OS) was 82%. Salvage treatments varied widely, including chemotherapy and radiotherapy (RT) (7), surgery and RT (3), and surgery, chemotherapy, and RT (3). On univariate analysis of PFS, symptoms at recurrence (P=0.04) and extranodal recurrences (P<0.01) were found to be statistically significant negative prognosticators for PFS. On univariate analysis of OS, increasing age at recurrence and presence of symptoms were found to have a trend toward statistically significant association with negative OS outcomes (P=0.08 and P=0.10, respectively). Conclusions: Our study demonstrates that long-term survival for pelvic or abdominal recurrences is possible with curative salvage therapy. The presence of symptoms is a negative prognostic factor in treatment outcome, and imaging may be effective for diagnosis in symptomatic and asymptomatic patients. Larger studies need to be performed to confirm these findings.

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

Abstract 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 cm3) compared to CTF (median 169 cm3, 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 cm3) and CTF (median 499 cm3, 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 Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target

BACKGROUND Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets. METHODS We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab. The primary outcome was distant metastasis-free survival (DMFS). Secondary outcomes included biochemical recurrence-free survival (bRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). All statistical tests were two-sided. RESULTS Unsupervised hierarchical clustering of hallmark pathways demonstrated an immune-related tumor cluster. Increased estimated immune content scores based on immune-specific genes from the literature were associated with worse bRFS (hazard ratio [HR] = 1.26 [95% confidence interval [CI] = 1.12 to 1.42]; P < .001), DMFS (HR = 1.34 [95% CI = 1.13 to 1.58]; P < .001), PCSS (HR = 1.53 [95% CI = 1.21 to 1.92]; P < .001), and OS (HR = 1.27 [95% CI = 1.07 to 1.50]; P = .006). Deconvolution using Cibersort revealed that mast cells, natural killer cells, and dendritic cells conferred improved DMFS, whereas macrophages and T-cells conferred worse DMFS. Interestingly, while PD-L1 was not prognostic, consistent with its low expression in prostate cancer, PD-L2 was expressed at statistically significantly higher levels (P < .001) and was associated with worse bRFS (HR = 1.17 [95% CI = 1.03 to 1.33]; P = .01), DMFS (HR = 1.25 [95% CI = 1.05 to 1.49]; P = .01), and PCSS (HR = 1.45 [95% CI = 1.13 to 1.86]; P = .003). PD-L2 was strongly associated with immune-related pathways on gene set enrichment analysis suggesting that it is playing an important role in immune modulation in clinical prostate cancer samples. Furthermore, PD-L2 was correlated with radiation response pathways, and also predicted response to postoperative radiation therapy (PORT) on multivariable interaction analysis (P = .03). CONCLUSION In the largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.

In-field and abscopal response after short-course radiation therapy in patients with metastatic Merkel cell carcinoma progressing on PD-1 checkpoint blockade: a case series

BackgroundPatients with metastatic Merkel cell carcinoma (mMCC) who experience disease progression on immunotherapy have limited additional standard options. Given evidence of synergism between radiation therapy (RT) and immunotherapy, two patients progressing on PD-1 inhibition were referred for short-course RT.Case presentationTwo patients were found to have progressive mMCC on PD-1 inhibitor therapy and were treated with single-fraction palliative RT. Both patients were observed to have local control at irradiated regions, as well as durable abscopal response at unirradiated, out-of-field, sites of metastatic disease.ConclusionsShort-course RT is a compelling strategy that could be a means to augment response in patients with mMCC who show progression on immune checkpoint blockade. Ongoing clinical trials are investigating the relationship between RT and immunotherapy in mMCC.

Proton Therapy Reduces Normal Tissue Dose in Extended-Field Pelvic Radiation for Endometrial Cancer

Purpose We dosimetrically compared pencil beam scanning (PBS) proton therapy and intensity-modulated radiation therapy (IMRT) for pelvic and para-aortic lymph node disease in endometrial carcinoma and present acute toxicities associated with extended-field PBS. Patients and Methods Twenty-five patients with locally advanced endometrial malignancies were enrolled in an image-guided registry study. Seven of these patients were treated with PBS, and 18 patients were treated with IMRT. Organs at risk included pelvic bone marrow (PBM), small bowel (SB), large bowel (LB), rectum, bladder, and kidneys. The IMRT and PBS dosimetric parameters were compared using Wilcoxon rank-sum tests. Results Compared with IMRT PBM dose-volume histograms, PBS resulted in significantly lower dose volumes from 0 to 26.0 Gy (P < .05) and higher dose volumes from 33.9 to 42.9 Gy (P < .05). Overall, PBS resulted in 22% lower median PBM volume irradiated to 10 Gy (RBE) (PBS 71.3% versus IMRT 93.4%, P < .001) and 14% lower median volume irradiated to 20 Gy (RBE) (PBS 65.1% versus IMRT 79.4%, P < .001). Compared with IMRT, PBS also significantly reduced SB dose volumes from 0 to 27.5 Gy, LB dose volumes from 0 to 31.6 Gy, bladder dose volumes from 0 to 27.3 Gy, and rectal dose volumes from 0 to 7.6 Gy (all P < .05). However, PBS resulted in higher rectal dose volumes compared with IMRT from 26.0 to 48.4 Gy. Grade 3+ hematologic toxicities were present in 2 (11%) IMRT-treated patients and no PBS-treated patients. No grade 3+ gastrointestinal or genitourinary toxicities were present in either treatment group. Conclusion In endometrial carcinoma, extended-field PBS is clinically feasible, resulting in statistically significant dose reduction to PBM as well as SB, LB, and bladder in the lower dose regions.