Combined modality management of advanced cervical cancer including novel sensitizers.

The management of advanced cervical cancer has evolved with time. Combined modality treatments for cervical cancer have been shown to improve clinical outcomes for these patients. The role of surgery is reviewed in this article for specific situations such as the treatment of bulky lymph nodes and even in the metastatic setting. External beam radiotherapy and brachytherapy techniques have improved which has decreased patient toxicity. Systemic therapy such as chemotherapy, immunotherapy, and novel sensitizing agents have been extensively studied and have shown promising results. The combination of these three different modalities of treatment can be tailored to each specific patient to achieve the best outcomes. We review the recent advances and various international guidelines for the management of cervical cancer in this article.

Outcomes of oesophageal cancer treated with neoadjuvant compared with definitive chemoradiotherapy.

INTRODUCTION: We report outcomes of patients with oesophageal cancer treated with neoadjuvant chemoradiotherapy (NACRT) plus surgery or definitive chemoradiotherapy (chemoRT) at our institution. METHODS: We retrospectively reviewed patients who underwent chemoRT from 2005 to 2017. The primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS) and toxicities. RESULTS: We identified 96 patients with median age of 64 years and squamous cell carcinoma in 82.3%. Twenty-nine patients (30.2%) received NACRT plus surgery, 67 patients (69.8%) received definitive chemoRT. Median follow-up was 13.5 months. The 3/5-year OS were 26.4%/13.4%, and 59.6%/51.6% in the definitive chemoRT and NACRT plus surgery groups, respectively. The 3/5-year DFS were 19.3%/12.3%, and 55.7%/37.2% in the definitive chemoRT and NACRT plus surgery groups, respectively. NACRT plus surgery significantly improved OS (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.22-0.72, P<0.01) and DFS (subhazard ratio [SHR] 5.21, 95 CI 1.20-22.7, P=0.03). Multivariable analysis for OS in the definitive chemoRT group indicated stage (1-2 vs 3-4a; HR 2.17, 95% CI 1.15-4.11, P=0.02) and feeding tube (no tube versus tube; HR 1.85, 95% CI 1.00-3.43, P=0.05) as significantly associated with OS. The cumulative incidence of local recurrence was significantly higher in the definitive chemoRT group (SHR 5.21, 95 CI 1.2022.7, P=0.03). Nineteen patients (65.5%) had postoperative complications. CONCLUSION: NACRT plus surgery improved OS and DFS. However, in view of treatment-related complications, careful selection of patients is warranted. With the predominant histology of our cohort being squamous cell carcinoma (SCC), our results may be more relevant for those with SCC.

Radiation oncology training in Singapore - A non-Australasian RANZCR training site.

The Radiation Oncology Department at The National Cancer Institute, Singapore (NCIS) and the Royal Australian and New Zealand College of Radiology (RANZCR) has had a well-established relationship that began as a partnership to grow a pool of local radiation oncologists to meet a nation's demand for radiotherapy services. This journey has surpassed its initial aims and now has produced a generation of radiation oncologists leading a national cancer institute. We recount the history and progress of this partnership here, as well as the unique success of its product; the only RANZCR-accredited radiation oncology training site outside of Australia and New Zealand since 2002. We outline the mutual benefits through many years of collaboration and deliberate efforts to grow the partnership. We also outline the distinctive specialist training path that our trainees take to meet both the local accreditation body as well as the RANZCR requirements.

Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01).

PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

Emerging radiotherapy technologies and trends in nasopharyngeal cancer.

Technology has always driven advances in radiotherapy treatment. In this review, we describe the main technological advances in radiotherapy over the past decades for the treatment of nasopharyngeal cancer (NPC) and highlight some of the pressing issues and challenges that remain. We aim to identify emerging trends in radiation medicine. These include advances in personalized medicine and advanced imaging modalities, standardization of planning and delineation, assessment of treatment response and adaptive re-planning, impact of particle therapy, and role of artificial intelligence or automation in clinical care. In conclusion, we expect significant improvement in the therapeutic ratio of radiotherapy treatment for NPC over the next decade.

Post mastectomy radiotherapy for elderly patients with intermediate risk (T1-2N1 OR T3N0) breast cancer: a systematic review and meta-analysis.

BACKGROUND: To determine if PMRT for elderly patients (>65 years old) with intermediate risk breast cancer (T1-2N1, T3N0) improves outcomes. METHODS: We performed a systematic review and meta-analysis to compare the effects of PMRT to no PMRT for elderly patients with intermediate-risk breast cancer. We searched PubMed for eligible studies from Jan 2008 to Dec 2018. We assessed the methodological quality of the included studies using the ROBINS-I tool and performed the meta-analysis with random effects model. The primary outcome of interest was overall survival (OS); secondary outcomes were breast cancer specific survival (BCSS), loco-regional (LRR) and distant disease recurrence (DDR). RESULTS: We found 2 retrospective cohort studies with 743 patients directly comparing PMRT to no PMRT. Both studies were judged to have serious risk of bias in their methodological quality. The pooled results suggest that PMRT was associated with a 20% relative reduction in the hazard in death, ranging from 41% relative reduction, a substantial negative association to 10% relative increase, a small positive association (HR 0.80, 95% CI: 0.59-1.1, P=0.62, I2=0%). PMRT was also associated with a 17% relative reduction in the hazard for breast cancer related death, ranging from 52% relative reduction, a substantial negative association to 41% relative increase, a substantial positive association (HR 0.83, 95% CI: 0.48-1.41, P=0.48, I2=0%). One study did not observe any significant differences in LRR and DDR between the two groups. CONCLUSIONS: The survival benefits from PMRT in unselected elderly patients with intermediate risk breast cancer is unclear. Further research to better select elderly patients who may benefit from PMRT is warranted. Patients with a multiple pathological risk factors suggestive of high risk of loco-regional recurrence post-mastectomy should consider PMRT.

Radiation therapy for rectal cancer.

Radiotherapy (RT) has remained an important pillar in the multi-modality management of rectal cancer. Adjuvant RT with concurrent chemotherapy (chemo-RT) was once the standard of care for locally advanced rectal cancer, but with time, that has now changed and neoadjuvant chemo-RT followed by total mesorectal excision (TME) surgery is the new standard. Alternatively, neoadjuvant RT alone remains an option and clinicians are tasked to choose between the two. In an era of personalised oncological management, it is unsurprising that the treatment for rectal cancer is following suit and upcoming trials are studying ways to improve outcomes and minimise toxicity for patients while tailoring treatments specific to each patient's tumour. We review the evolution of the role of RT in rectal cancer and look forward to what the future holds.

Quality of head and neck radiotherapy reporting in randomized controlled trials.

BACKGROUND: The purpose of this clinical review was to determine the quality reporting of radiotherapy (RT) in randomized controlled trials (RCTs) of head and neck cancer and its impact on reporting of the trial primary efficacy and toxicity outcomes. METHODS: We searched MEDLINE for eligible RCTs published between 1994 and 2015. We assessed the quality of RT reporting and bias in the reporting of trial outcomes using published criteria. RESULTS: We found 67 eligible trial reports. There was significant variability in the quality of RT treatment reporting among the included trials. Thirty-two trials had adequate quality RT reporting. Cooperative group trials were more likely to have adequate quality reporting (odds ratio [OR] 3.02; 95% confidence interval [CI] 1.04-9.85). The quality of RT reporting did not influence the bias in the reporting of trial outcomes. CONCLUSION: The quality of head and neck RT reporting in RCTs is variable and did not impact on bias in reporting of trial outcomes.

Outcomes of neoadjuvant chemoradiotherapy followed by total mesorectal excision surgery for locally advanced rectal cancer: a single-institution experience.

INTRODUCTION: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery for locally advanced rectal cancer has been shown to improve local control and reduce toxicity, as compared to adjuvant CRT. We reported the outcomes of our patients with locally advanced rectal cancer treated at National University Hospital, Singapore. METHODS: From April 2002 to December 2014, 117 patients with T3/4, N0/+, M0 rectal cancer received neoadjuvant CRT followed by TME surgery. The treatment regimen comprised a total radiotherapy dose of 50.4 Gy in 28 daily fractions delivered concurrently with 5-fluorouracil or capecitabine chemotherapy over 5.5 weeks. All patients were planned for TME surgery. Local control, disease-free survival, overall survival and treatment toxicities were analysed. RESULTS: Median follow-up was 34 (range 2-122) months. 11.5% (13/113) of patients achieved a pathological complete response (pCR) and 72.6% (85/117) had either tumour or nodal downstaging following neoadjuvant CRT. 5.2% (5/96) of patients had Grade 3 acute toxicities (dermatitis and diarrhoea) and 3.1% (3/96) had Grade 3 late toxicities (fistula and stricture). There was no Grade 4 toxicity noted. The five-year local recurrence, disease-free survival and overall survival rates were 4.5%, 65.7% and 80.6%, respectively. Multivariate analysis showed that nodal positivity was a predictor of poor disease-free survival and poor overall survival. Tumour downstaging and pCR did not improve outcomes. CONCLUSION: Our outcomes were comparable to internationally published data, and this treatment regimen remains the standard of care for locally advanced rectal cancer in our local population.

Outcomes of Asian patients with localized prostate cancer treated with combined intensity modulated radiation therapy (IMRT) and high dose rate (HDR) brachytherapy: A single institution experience.

AIM: External beam radiotherapy (EBRT) followed by high dose rate (HDR) brachytherapy boost has demonstrated minimal toxicities and improved disease control rate compared with EBRT alone in observational and randomized studies with predominantly Caucasian patients. This study aims to report the outcomes of patients treated with this approach in our predominantly Asian population. METHODS: Medical records for patients with localized prostate cancer who received combined EBRT delivered via intensity modulated radiotherapy (IMRT) technique followed by HDR brachytherapy boost were retrospectively reviewed. Outcomes evaluated included 5-year biochemical recurrence-free survival (per Phoenix definition), overall survival and treatment toxicities. RESULTS: From June 2009 to March 2015, 75 patients were treated with IMRT followed by HDR brachytherapy boost. Twenty patients (27%) had intermediate risk, 55 (74%) had high-risk disease. Median follow up was 64 months. All patients received IMRT to a median dose of 45 Gy to the pelvis followed by HDR brachytherapy boost. Sixty, 10 and 5 patients received boost of 21 Gy in two fractions, 19 Gy in two fractions and 15 Gy in a single fraction, respectively. All patients met the planning criteria adapted from RTOG 0815. The 5-year prostate-specific antigen (PSA) control was 85.2% (80.3% and 100% for high-risk and intermediate-risk group, respectively). Cancer-specific survival and overall survival are 97.3% and 92.0%, respectively. Eleven (15%) patients developed biochemical failure, six of which had distant metastasis. Three (4%) developed grade 3 genitourinary toxicity (urethral stricture and/or cystitis) and none developed grade 3 radiation proctitis. CONCLUSION: Our outcomes are comparable to internationally published data and demonstrate reproducibility of this approach in our population.

Life-threatening Bleed Secondary to Tumor Shrinkage Effectively Palliated with Radiotherapy.

Inverted papilloma is a typically benign, but locally aggressive tumor arising from the nasal cavity and paranasal sinuses. Malignant transformation can occur in up to 10% of cases. Although spontaneous tumor bleeding can occur with malignancies, hemorrhage secondary to tumor shrinkage has not been reported. We present a patient with metastatic squamous cell carcinoma (from inverted papilloma) who developed a life-threatening bleed shortly after chemotherapy initiation. She was managed successfully with life-saving palliative radiotherapy (RT), delivered based on clinical markup. She was subsequently re-treated with highly conformal RT and chemotherapy to achieve a marked clinical response without surgery.

Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible to HIV infection.

CD4+CD25+ human regulatory T cells (Treg cells), which express the transcription factor FoxP3, suppress T cell activation. In this study, we sought to define cellular and molecular mechanisms of human Treg cell differentiation. A subset of human naive CD4+ T cells that are CD25+ express high levels of FoxP3. We show that upon activation through the TCR, these FoxP3-expressing naive T cells (termed TNreg cells) greatly expand in vitro. Expanded TNreg cells acquire a full Treg phenotype with potent suppressive activity and display low IL-2 production upon TCR stimulation. TNreg cells in which FoxP3 expression was reduced through RNA interference lost their suppressive activity, but retained their low IL-2 secretion in response to TCR stimulation. Furthermore, in support of the notion that TNreg cells represent a separate lineage of naive cells, we found that they were more susceptible to HIV infection as compared with naive CD4+ T cells. Based on these findings, we propose that TNreg cells are precursors for human Treg cells and that these cells require a high level of FoxP3 expression to maintain their suppressive function. Accordingly, modulation of TNreg cell numbers during infections such as HIV may disrupt human Treg cell development, and contribute to chronic immune activation.

Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are caused by activating mutations of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases. GISTs can be successfully treated with imatinib mesylate, a selective small-molecule protein kinase inhibitor that was first clinically approved to target the oncogenic BCR-ABL fusion protein kinase in chronic myelogenous leukemia, but which also potently inhibits KIT and PDGFR family members. The mechanistic events by which KIT/PDGFRA kinase inhibition leads to clinical responses in GIST patients are not known in detail. We report here that imatinib triggers GIST cell apoptosis in part through the up-regulation of soluble histone H2AX, a core histone H2A variant. We found that untreated GIST cells down-regulate H2AX in a pathway that involves KIT, phosphoinositide-3-kinase, and the ubiquitin/proteasome machinery, and that the imatinib-mediated H2AX up-regulation correlates with imatinib sensitivity. Depletion of H2AX attenuated the apoptotic response of GIST cells to imatinib. Soluble H2AX was found to sensitize GIST cells to apoptosis by aberrant chromatin aggregation and a transcriptional block. Our results underscore the importance of H2AX as a human tumor suppressor protein, provide mechanistic insights into imatinib-induced tumor cell apoptosis and establish H2AX as a novel target in cancer therapy.

Human natural killer T cells are heterogeneous in their capacity to reprogram their effector functions.

BACKGROUND: Natural killer T (NKT) cells are a subset of T cells that help potentiate and regulate immune responses. Although human NKT cell subsets with distinct effector functions have been identified, it is unclear whether the effector functions of these subsets are imprinted during development or can be selectively reprogrammed in the periphery. RESULTS: We found that neonatal NKT cells are predominantly CD4+ and express higher levels of CCR7 and CD62L and lower levels of CD94 and CD161 than adult CD4+ or CD4- NKT cell subsets. Accordingly, neonatal NKT cells were more flexible than adult CD4+ NKT cells in their capacity to acquire Th1- or Th2-like functions upon either cytokine-mediated polarization or ectopic expression of the Th1 or Th2 transcription factors T-bet and GATA-3, respectively. Consistent with their more differentiated phenotype, CD4- NKT cells were predominantly resistant to functional reprogramming and displayed higher cytotoxic function. In contrast to conventional T cells, neither the expression of CXCR3 nor the cytotoxic capacity of neonatal NKT cells could be reprogrammed. CONCLUSIONS AND SIGNIFICANCE: Together, these results suggest that neonatal CD4+, adult CD4+, and adult CD4- NKT may represent unique states of maturation and that some functions of human NKT cells may be developmentally imprinted, while others are acquired similar to conventional T cell subsets during peripheral maturation and differentiation. Given the potent immuno-regulatory functions of NKT cells, these findings have important implications for the development of novel NKT cell-based therapeutics and vaccines.

A role of the mitotic spindle checkpoint in the cellular response to DNA replication stress.

Replication stress is a frequent and early event during tumorigenesis. Whereas the cellular responses to a persistent block of replication fork progression have been extensively studied, relatively little is known about how cells respond to low-intensity replication stress. However, transient replication fork perturbations are likely to occur even more frequently in tumor cells than a permanent replication arrest. We report here that transient, low intensity replication stress leads to a rapid activation of the DNA replication checkpoint but to a significantly delayed apoptotic response in a small but significant number of cells. This late apoptotic response was independent of p53 and we found evidence for cell death during mitosis in a proportion of cells. To further explore the role of p53 in the response to replication stress, we analyzed mouse embryonic fibroblasts (MEFs) deficient of p53 in comparison to wild-type or p63- or p73-deficient MEFs. We detected a significant increase of apoptosis and morphological signs of failed mitosis such as multinucleation in p53-deficient MEFs following replication stress, but not in wild-type or p63- or p73-deficient cells. Multinucleated p53-deficient MEFs frequently retained cyclin B1 expression indicating a persistently activated mitotic spindle checkpoint. Collectively, our results suggest that the cellular response to replication stress involves the mitotic spindle checkpoint in a proportion of cells. These findings imply that the mitotic spindle checkpoint may act in concert with DNA damage and cell-cycle checkpoints as an early anti-tumor barrier and provide a possible explanation for its frequent relaxation in human cancer.