High-dose selenium (Se) as selenomethionine (SLM) and sodium selenite (SS) can improve the efficacy of cancer therapies while reducing toxicity. Se-methylselenocysteine (MSC) is effective in preclinical models but has not been evaluated in cancer trials. This phase Ib randomised, double-blinded trial explored the safety, pharmacokinetics (PK) and selected pharmacodynamic (PD) mechanisms of MSC, SLM and SS to guide future trials. Nine participants with metastatic cancer took Se 1600 μg/day for 4 weeks, then 6400 μg/day for 4 weeks, as MSC, SLM, or SS, with safety, PK, and PD assessments at baseline then every 4 weeks for 12 weeks. No dose-limiting toxicities occurred, and all adverse events were grades 1-2, mainly gastrointestinal. Total plasma Se increased after 8 weeks to mean 27.2 μM with SLM, 4.14 μM with MSC and 3.90 μM with SS. No significant changes in DNA damage or intracellular glutathione were observed in peripheral blood mononuclear cells. Mean plasma selenoprotein P (SEPP) increased from 3.74 mg/L at baseline to 4.66 mg/L and 5.13 mg/L after 4 and 8 weeks (p = 0.136 and 0.104, respectively). More detailed evaluations of safety, PK and PD mechanisms are needed to determine a recommended Se compound and dose for larger trials in combination with cancer therapies.

Background:Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype, has a median overall survival of 11-14 months despite standard treatment. Ketogenic metabolic interventions that lower the glucose ketone index (GKI) may improve outcomes. We evaluated the feasibility, tolerability, and potential clinical benefit of integrating standard treatment with an intensive multimodal metabolic therapy program (MTP) in newly diagnosed IDH-wildtype GBM. Methods:Patients received standard chemoradiation and adjuvant chemotherapy alongside an MTP comprising prolonged fasting, time-restricted feeding, and a ketogenic diet. The primary outcome was the proportion sustaining a mean daily GKI ≤6 during chemoradiation. Secondary outcomes included GKI control throughout chemotherapy, body weight, body mass index, adverse events, performance, exercise, quality of life, and survival, compared with contemporary controls using unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results:Among 32 eligible patients, 18 commenced chemoradiation with the MTP (intention-to-treat), and 15 completed it (per-protocol). In the intention-to-treat population, 15 of 18 patients (83%) sustained a mean daily GKI ≤6 during chemoradiation. Among per-protocol patients, the GKI was 1.88 ± 0.56 during chemoradiation and 2.53 ± 0.86 throughout chemotherapy. Intentional weight loss averaged 17%, normalizing body mass index. MTP-related adverse events were mild or moderate. Exercise activity and quality of life improved. Median overall survival was 21.5 months versus 14.7 months in controls (HR = 0.42, 95% CI 0.18-0.97, P = .027), with 3-year survival of 27% versus 7%. Conclusions:Intensive multimodal metabolic therapy was feasible, well-tolerated, and associated with improved exercise activity, quality of life, and survival outcomes, including higher 3-year survival.

This work presents the first systematic comparison of selenium (Se) speciation in plasma from cancer patients treated orally with three Se compounds (sodium selenite, SS; L-selenomethionine, SeMet; or Se-methylselenocysteine, MSC) at 400 µg/day for 28 days. The primary goal was to investigate how these chemical forms of Se affect the plasma Se distribution, aiming to identify the most effective Se compound for optimal selenoprotein expression. This was achieved using methodology based on HPLC-ICP-MS after sample preparation/fractionation approaches. Measurements of total Se in plasma samples collected before and after 4 weeks of treatment showed that median total Se levels increased significantly from 89.6 to 126.4 µg kg−1 Se (p < 0.001), particularly when SeMet was administered (190.4 µg kg−1 Se). Speciation studies showed that the most critical differences between treated and baseline samples were seen for selenoprotein P (SELENOP) and selenoalbumin after administration with MSC (p = 5.8 × 10−4) and SeMet (p = 6.8 × 10−5), respectively. Notably, selenosugar-1 was detected in all low-molecular-weight plasma fractions following treatment, particularly with MSC. Two different chromatographic approaches and spiking experiments demonstrated that about 45

PDF - 94K, Detailed mixed models analysis of self-reported and biomarker data.

Rectal cancer is a common malignancy. The management of rectal cancer has recently evolved and has undergone a paradigm shift with the advent of treatment approaches such as total neoadjuvant therapy and the watch-and-wait approach. However, despite the recently available evidence, there is no consensus on the optimal management approach in the setting of locally advanced rectal cancer. To address some of the controversies, a joint multidisciplinary panel discussion was conducted at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting in November 2022. Members from different subspecialties formed two panels and discussed three clinical cases in a debate format. Each case represented some of the complex issues faced by clinicians in this setting. The discussion is now presented in this manuscript, which depicts the different available management approaches and reiterates the importance of a multidisciplinary approach.

We live in uncertain times. New discoveries and knowledge collectively challenge us to reconsider the wisdom of previously accepted dogma. This is the situation currently faced by clinicians and patients following recent reporting of several large randomized clinical trials (RCTs) on the management of locally-advanced rectal carcinoma (LARC). Validation of a treatment concept takes many years, first evaluated in smaller trials before progressing to RCTs, and multiple questions are explored by different research groups, often in parallel. When these come to fruition at the same time, clinicians and patients may be confronted with a quick succession of practice-changing answers from clinical trials to questions that they may not know had been asked. The more familiar questions are traditional RCT designs that compare an investigational treatment against a control treatment in patients with similar baseline risk factors. A significant benefit in the investigational arm may lead to a change in “standard of care” that incrementally improves outcomes when applied to similar patients. This “one size fits all” approach to patient management is reflected in much of our current practice.1, 2 However, more recent innovative questions ask how to optimize treatment for individual patients to maximize their cancer-related outcomes while minimizing the treatment needed to achieve this, thereby avoiding its adverse consequences. Yet the ability to answer the “individualized patient treatment” questions relies on the efficacy of improved treatments developed by the “one size fits all” trials; clearly, both are needed. An early example of an innovative practice change to a more individualized approach is the “watch and wait” rectal preservation strategy, which arose not from RCTs but from surgeons asking how to most benefit each patient in their clinical practice.3 This strategy was offered to LARC patients who achieved a near-complete or complete clinical response (cCR) to neoadjuvant treatment. While this was initially greeted with caution, cumulative clinical evidence showed this to be effective in reducing the proportion of patients who (would have normally) required major surgery, without increasing local or distant failure.3 The enthusiasm from patients and surgeons alike for this “watch and wait” approach led to its incorporation into clinical guidelines, despite the lack of phase 3 RCT evidence to support this.1, 2 However, strategies to increase the proportion of patients eligible for this approach are being evaluated in prospective clinical trials, incorporating key outcome measures agreed by international consensus.3 Unlike the slow acculturation of this approach, the concept of total neoadjuvant therapy (TNT) proved to be a major disruption. The “standard” management for LARC for over a decade has been either short-course radiotherapy (SCRT; 25 Gy radiation over 5 days) or “long-course” concurrent chemotherapy and radiotherapy (CRT; variations around 50 Gy radiation over 5 weeks), followed by total mesorectal excision (TME) surgery 6–12 weeks later.1, 2 Adjuvant chemotherapy, while not proven to improve overall survival (OS), is commonly added for patients with high risk of relapse.1, 2 TNT, in contrast, shifts chemotherapy into the neoadjuvant treatment phase, either prior to (induction) or following (consolidation) SCRT or CRT, or both (“sandwich”).4 Earlier introduction of chemotherapy is hypothesized to improve: (1) chemotherapy delivery overall (without compromising SCRT, CRT or surgical morbidity), (2) tumor regression and downstaging, (3) R0 resection rates, (4) sphincter and rectal preservation rates, (5) local and distant relapse rates, and (6) disease-free and OS.4 Adjuvant chemotherapy is omitted or shortened.4 The appeal of TNT prompted its early adoption into clinical practice (giving rise to multiple retrospective and prospective uncontrolled studies) as well as RCTs, only some of which included a standard treatment control arm. A comprehensive review in this journal of all TNT studies in LARC presented or published up to July 2021 is therefore timely and welcomed and highlights the wide range of questions being evaluated.4 Three questions were at least partially answered by RCTs presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Scientific Meeting (ASM). PRODIGE 23 (n = 461) asked whether 12 weeks of induction chemotherapy (oxaliplatin-fluoropyrimidine [OX-FP] with irinotecan) before CRT, followed by surgery then 3 months of adjuvant chemotherapy, improved the primary endpoint of disease-free survival (DFS), compared to standard treatment (CRT/TME/adjuvant chemotherapy).5 RAPIDO (n = 912) compared SCRT followed by 18 weeks of consolidation OX-FP chemotherapy then TME, to standard treatment, with a primary endpoint amended from DFS to disease-related treatment failure (DRTF).6 In contrast, OPRA (n = 324) had TNT in both arms: 4 months of induction or consolidation OX-FP chemotherapy, with CRT, and aimed to detect a 10% improvement in 3-year DFS in either treatment arm compared to a 75% historical rate.7 Patients who achieved a cCR, or near-cCR, were offered a “watch and wait” strategy, the remainder had TME surgery. PRODIGE 23 and RAPIDO both reported approximately 7% improvement in 3-year DFS or DRTF, respectively and in distant metastasis rates. There was also a 14%–16% increase in pathological complete response (pCR) rates but no OS difference.5, 6 Greater delivery of chemotherapy was achieved with acceptable toxicity (including operative outcomes) and no significant difference in locoregional failure. OPRA reported no improvement in DFS in either arm, but 59% and 43% of patients remained TME-free at 3 years in the consolidation and induction cohorts, respectively.7 At the 2021 ASCO ASM OPRA reported 3-year organ preservation rates of 78%, 45%, and 7% for patients with cCR (n = 124), near-cCR (n = 114), and incomplete (n = 55) clinical response, respectively.8 Clinical response was associated with significant differences in DFS, local recurrence-free, and metastasis-free survival. However, other RCTs evaluating similar TNT strategies have not confirmed these results.4 POLISH II (n = 541)9 and STELLAR (n = 599)10 investigated a similar strategy to RAPIDO, with consolidation OX-FP chemotherapy after SCRT for 6 and 12 weeks, respectively, followed by TME +/− adjuvant chemotherapy. Neither study showed improvements with TNT in pCR, DFS, local failure, or distant metastases, and although both reported significant improvement in 3-year OS, this OS difference in POLISH-II was lost at 8 years.9, 10 Similar to PRODIGE 23, GCR-3 (n = 102) compared 3 months of OX-FP chemotherapy prior to CRT then TME to standard treatment.11 No improvement was seen in rates of pCR, distant metastases, local recurrence, 5-year DFS, or OS. Comparable to OPRA is CAO/ARO/AIO-12 (n = 306), which used 6 weeks of induction or consolidation OX-FP chemotherapy with CRT.12 The consolidation cohort achieved the prespecified 25% pCR rate, but the induction cohort did not (17%); pathological downstaging was similar between the arms. In contrast, a nonrandomized trial (n = 259) reported improved tumor regression and DFS with increasing duration (0, 4, 8, or 12 weeks) of consolidation OX-FP chemotherapy after CRT.13 Deciding how these trials collectively inform patient management is challenging because they differ in important respects, including patient risk, the timing, duration, and regimen of chemotherapy, the use of SCRT or CRT, time from radiation to surgery, the option of organ preservation, and adjuvant chemotherapy.4 While some trials are not fully reported (including OPRA), others are reporting new or updated results in quick succession, resulting in meta-analyses of TNT studies published a few months apart drawing different conclusions.14, 15 But there are other questions arising from these trials. While the RAPIDO and PRODIGE 23 strategies increased the proportion of good responders, and oncological outcomes for the whole cohort, what impact could their strategies have on organ preservation, especially given the advantage of consolidation over induction chemotherapy in OPRA?5-7 And could the 25%–40% of patients who have a good response to CRT alone avoid the additional toxicity of TNT?5, 6, 16, 17 Similarly, in OPRA, did all patients need neoadjuvant chemotherapy, when a substantial minority remain TME-free after CRT alone?3 And are there options to improve outcomes for poor responders to TNT? These and other questions are being investigated in trials aiming to individualize treatment for patients to maximize oncological outcomes while minimizing treatment modalities, and their adverse consequences on quality of life.4 While OPRA and other trials are asking if surgery can be avoided,3 what about omitting CRT? FOWARC (n = 495) asked, in part, whether CRT could be safely omitted after induction OX-FP chemotherapy, compared to two arms with five cycles of FP or OX-FP chemotherapy overlapping with CRT (with surgery then adjuvant chemotherapy in all arms).18 The final report showed similar DFS, OS, R0 resection, and local recurrence rates in all arms, despite less tumor regression with the non-CRT arm, but greatly improved anal function without CRT. Other RCTs trials addressing this question include NORAD01-GRECCAR 16 (n = 574), which compares induction OX-FP-irinotecan chemotherapy to intensified CRT, prior to surgery,19 and PROSPECT (n = 1194), which asks whether CRT can be safely omitted in good responders to induction chemotherapy, compared to standard treatment.20 What about improving outcomes for poor responders to neoadjuvant treatment? GRECCAR 4 (n = 206) showed the safety and feasibility of using response to induction chemotherapy to tailor subsequent treatment, including omitting or intensifying CRT in good and poor responders, respectively, and a larger RCT, GRECCAR 14, is planned.21 Observations from earlier studies could also inform future strategies, such as timing of surgery after CRT. A retrospective Italian study of 1064 poor responders to CRT reported worse outcomes (including OS) if surgery was delayed >8 weeks.16 While GRECCAR-6 (n = 265) showed no difference in oncological outcomes by treatment response when surgery was performed 7 or 11 weeks after CRT,22 an ongoing RCT (n = 340) comparing surgery 8 or 12 weeks after CRT may help to clarify this question.23 The role of adjuvant chemotherapy in poor responders has not been resolved either, with its administration in poor responders in the Italian study showing improved OS compared to those not treated with it, an observation supported by pooled and meta-analysis of other trials.16, 24-26 Prospective (or retrospective) determination of the neoadjuvant rectal score in randomized trials might help to determine whether poor responders to CRT benefit from adjuvant chemotherapy.26, 27 Tailoring treatment according to response requires sensitive and specific methods to assess this, and appropriate endpoints for such studies.3, 28 Magnetic resonance imaging (MRI) is the mainstay of nonpathological response assessment, with several methods, including MRI-based tumor regression grading, under evaluation in prospective trials to optimize its contribution.3, 29, 30 It will be interesting to see the (currently unreported) results of MRI at the end of induction chemotherapy in PRODIGE 23.5 MRI is more informative when repeated at multiple timepoints during neoadjuvant treatment,3, 31 and assessing plasma circulating tumor DNA at similar timepoints provides complementary information.32, 33 Furthermore, prospective evaluation is warranted of tumor-infiltrating lymphocytes as a biomarker, as they appear to be prognostic, as well as predictive of response to neoadjuvant treatment, in LARC.34 So how do clinicians distil this information to determine optimal treatment options for each patient, according to the goals of treatment? We may not find much comfort in updated clinical practice guidelines, as inclusion of the PRODIGE 23, RAPIDO, and OPRA TNT strategies has only added to the diversity of management options, reflecting current uncertainties.1, 2 If the PROSPECT trial,20 which is due to report imminently, confirms that CRT can safely be omitted in good responders to induction chemotherapy, then clinicians and patients may find the choices even more challenging: is the priority organ preservation with avoidance of surgery, avoidance of pelvic radiation or is it cancer-free survival? In the absence of direct comparisons of these strategies, TNT is truly raising more questions than answers.

Background Glioblastoma multiforme (GBM) may be susceptible to metabolic strategies such as fasting and ketogenic diets, which lower blood glucose and elevate ketones. Combining these two strategies may be an ideal approach for sustaining a potentially therapeutic glucose ketone index (GKI). In this prospective case series, we observed whether a combined metabolic strategy was feasible, safe, and capable of sustaining a GKI <6 in patients with GBM. Methods We provided recommendations and guidelines to 10 GBM patients at various stages of tumour progression and treatment that enabled them to complete a 5–7-day fast every 1–2 months combined with a modified ketogenic diet during the intervening weeks. Patients monitored their blood glucose and ketone levels and body weight. Adverse effects were assessed. Results Patients completed a mean of 161 ± 74 days of the combined metabolic strategy, with 34 ± 18 (21%) days of prolonged fasting (mean fast duration: 6.0 ± 1.4 days) and 127 ± 59 (79%) days on the ketogenic diet. The mean GKI for all 10 patients was 3.22 (1.28 during the fasts, 5.10 during the ketogenic diet). Body weight decreased by 8.4 ± 6.9 kg (11.2% decrease in baseline weight). The most common adverse effects attributed to the fasts and ketogenic diet were fatigue, irritability, and feeling lightheaded. The metabolic strategy did not interfere with standard oncological treatments. Conclusion This is the first study to observe the feasibility and safety of repeated, prolonged fasting combined with a modified ketogenic diet in patients with GBM. Using minimal support, patients maintained the combined metabolic strategy for 5–6 months while sustaining a potentially therapeutic mean GKI of 3.22. Weight loss was considerable. Adverse effects attributed to the metabolic strategy were mild, and it did not interfere with standard oncological treatments. Study Registration: This study is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12620001310954. The study was registered on 4 December 2020.

Importance People with type 2 diabetes have greater risk for some site-specific cancers, and risks of cancers differ among racial and ethnic groups in the general population of Aotearoa New Zealand. The extent of ethnic disparities in cancer risks among people with type 2 diabetes in New Zealand is unclear. Objective To compare the risks of 21 common adult cancers among Māori, Pasifika, and New Zealand European individuals with type 2 diabetes in New Zealand from 1994 to 2018. Design, Setting, and Participants This population-based, matched cohort study used data from the primary care audit program in Auckland, New Zealand, linked with national cancer, death, and hospitalization registration databases, collected from January 1, 1994, to July 31, 2018, with follow-up data obtained through December 31, 2019. Using a tapered matching method to balance potential confounders (sociodemographic characteristics, lifestyle, anthropometric and clinical measurements, treatments [antidiabetes, antihypertensive, lipid-lowering, and anticoagulant], period effects, and recorded duration of diabetes), comparative cohorts were formed between New Zealand European and Māori and New Zealand European and Pasifika individuals aged 18 years or older with type 2 diabetes. Sex-specific matched cohorts were formed for sex-specific cancers. Exposures Māori, Pasifika, and New Zealand European (reference group) ethnicity. Main Outcomes and Measures The incidence rates of 21 common cancers recorded in nationally linked databases between 1994 and 2018 were the main outcomes. Weighted Cox proportional hazards regression was used to assess ethnic differences in risk of each cancer. Results A total of 33 524 adults were included: 15 469 New Zealand European (mean [SD] age, 61.6 [13.2] years; 8522 [55.1%] male), 6656 Māori (mean [SD] age, 51.2 [12.4] years; 3345 [50.3%] female), and 11 399 Pasifika (mean [SD] age, 52.8 [12.7] years; 5994 [52.6%] female) individuals. In the matched New Zealand European and Māori cohort (New Zealand European: 8361 individuals; mean [SD] age, 58.9 [12.9] years; 4595 [55.0%] male; Māori: 5039 individuals; mean [SD] age, 51.4 [12.3] years; 2542 [50.5%] male), significant differences between New Zealand European and Māori individuals were identified in the risk for 7 cancers. Compared with New Zealand European individuals, the hazard ratios (HRs) among Māori individuals were 15.36 (95% CI, 4.50-52.34) for thyroid cancer, 7.94 (95% CI, 1.57-40.24) for gallbladder cancer, 4.81 (95% CI, 1.08-21.42) for cervical cancer (females only), 1.97 (95% CI, 1.30-2.99) for lung cancer, 1.81 (95% CI, 1.08-3.03) for liver cancer, 0.56 (95% CI, 0.35-0.90) for colon cancer, and 0.11 (95% CI, 0.04-0.27) for malignant melanoma. In the matched New Zealand European and Pasifika cohort (New Zealand European: 9340 individuals; mean [SD] age, 60.6 [13.1] years; 4885 [52.3%] male; Pasifika: 8828 individuals; mean [SD] age, 53.1 [12.6] years; 4612 [52.2%] female), significant differences between New Zealand European and Pasifika individuals were identified for 6 cancers. Compared with New Zealand European individuals, HRs among Pasifika individuals were 25.10 (95% CI, 3.14-200.63) for gallbladder cancer, 4.47 (95% CI, 1.25-16.03) for thyroid cancer, 0.48 (95% CI, 0.30-0.78) for colon cancer, 0.21 (95% CI, 0.09-0.48) for rectal cancer, 0.21 (95% CI, 0.07-0.65) for malignant melanoma, and 0.01 (95% CI, 0.01-0.10) for bladder cancer. Conclusions and Relevance In this cohort study, differences in the risk of 21 common cancers were found between New Zealand European, Māori, and Pasifika groups of adults with type 2 diabetes in New Zealand from 1994 to 2018. Research into the mechanisms underlying these differences as well as additional screening strategies (eg, for thyroid and gallbladder cancers) appear to be warranted.

HBI-8000 also known as tucidinostat is an orally bioavailable, low-nanomolar inhibitor of cancer-associated histone deacetylase enzymes. HBI-8000 is a histone deacetylase inhibitor (HDACi), and as an epigenetic regulator modulating the gene expression, without changing the DNA sequence. HBI-8000 is being developed as a monotherapy for the treatment of hematological malignancies and in combinations for the treatment of solid tumors such as melanoma, breast, kidney, and lung cancers.

PURPOSE:Predicting short-term mortality in patients with advanced cancer remains challenging. Whether digitalized clinical text can be used to build models to enhance survival prediction in this population is unclear. MATERIALS AND METHODS:We conducted a single-centered retrospective cohort study in patients with advanced solid tumors. Clinical correspondence authored by oncologists at the first patient encounter was extracted from the electronic medical records. Machine learning (ML) models were trained using narratives from the derivation cohort, before being tested on a temporal validation cohort at the same site. Performance was benchmarked against Eastern Cooperative Oncology Group performance status (PS), comparing ML models alone (comparison 1) or in combination with PS (comparison 2), assessed by areas under receiver operating characteristic curves (AUCs) for predicting vital status at 11 time points from 2 to 52 weeks. RESULTS:ML models were built on the derivation cohort (4,791 patients from 2001 to April 2017) and tested on the validation cohort of 726 patients (May 2017-June 2019). In 441 patients (61%) where clinical narratives were available and PS was documented, ML models outperformed the predictivity of PS (mean AUC improvement, 0.039, P < .001, comparison 1). Inclusion of both clinical text and PS in ML models resulted in further improvement in prediction accuracy over PS with a mean AUC improvement of 0.050 (P < .001, comparison 2); the AUC was > 0.80 at all assessed time points for models incorporating clinical text. Exploratory analysis of oncologist's narratives revealed recurring descriptors correlating with survival, including referral patterns, mobility, physical functions, and concomitant medications. CONCLUSION:Applying ML to oncologists' narratives with or without including patient's PS significantly improved survival prediction to 12 months, suggesting the utility of clinical text in building prognostic support tools.

BACKGROUND:Radiotherapy (RT) for oropharyngeal squamous cell cancer (OPSCC) is associated with malnutrition due to treatment-related mucositis and dysphagia. While percutaneous endoscopic gastrostomy (PEG) feeding can improve nutrition, it has acute and late complications, including dependence on PEG feeding. We retrospectively evaluated patient outcomes by whether gastrostomy placement was prophylactic (P-G) or reactive to RT complications (R-G).METHODS:Retrospective analysis of OPSCC patients undergoing curative-intent RT at Waikato Hospital between 2010 and 2015.RESULTS:Of 103 OPSCC patients treated with RT (+/- chemotherapy) 21 had P-G, 15 had R-G and 67 had none (No-G). P-G patients were significantly more likely to be female, older, have higher tumour stage and receive bilateral RT (all p < 0.05). P-G and No-G patients had similar rates and duration of hospital admission for complications during treatment, but both were significantly less than in R-G patients (admission rates 52.3%, 49.3% and 86.7%, and mean length of stay 3.5, 3.3 and 11.9 days, respectively; p < 0.001). R-G patients also had greater RT treatment delays than P-G or No-G patients (mean 1.1, 0.7 and 0.4 days, respectively, p < 0.05). No significant differences were noted between groups in PEG dependence or weight change during, or 1, 3 or 6 months after, RT. Weight loss was not significantly different with P-G than R-G despite more frequent use of bilateral RT fields in the former group.CONCLUSIONS:P-G placement affords shorter and less frequent hospital admissions than R-G during RT for OPSCC, with no increased complications or gastrostomy-dependence rates.

Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long‐term safety data.

Electronic medical records (EMR) represent a rich informatics resource that remains largely unexploited for improving healthcare outcomes. Here we report a systematic text mining analysis of EMR correspondence for 4791 cancer patients treated between 2001 and 2017. Meaningful groups of text descriptors correlating with poor survival outcomes were systematically identified, and applying machine learning analysis to clinical text accurately predicted cancer patient survival at selected timepoints up to 12 months. In a validation cohort of 726 patients, inclusion of EMR descriptors to machine learning models outperformed the predictivity of conventional clinical symptom scores by 4.9% (p = 0.001). These results prove that labour-intensive EMR data collection can be repurposed to add clinical value. Extension of this approach to a broader spectrum of digital health data should transform the real-time utility of such latent informatics resources, enabling healthcare systems to be more adaptive and responsive to patient circumstances.

BACKGROUND:The testicular cancer incidence in New Zealand is rising. We evaluated if testicular cancer outcomes differed by ethnicity in NZ. AIMS:To study if ethnic disparities existed among testicular cancer patients and their outcomes treated at Waikato Regional Cancer Centre. METHODS:Retrospective review of testicular cancer cases in the Medical Oncology database, Waikato Hospital, between 2001 and 2013 inclusive. RESULTS:Three hundred and twenty-five patients were seen, with median follow up of survivors being 101 (range 13-230) months. 95 (29.2%) were Māori, 210 (64.6%) NZ European and 20 (6.1%) of other ethnicity. One hundred and eighty-two patients were diagnosed with seminoma and 143 with non-seminoma. Māori represented 27.5% of seminoma and 31.4% of non-seminoma patients. Median age at diagnosis was 39 years for seminoma and 30 years for non-seminoma; Māori were significantly younger than non- Māori for both seminoma (median age 35 versus 42 years) and non-seminoma (median age 28 vs 34 years, respectively). While stage distribution of seminoma at diagnosis was similar for Māori and non-Māori (chi-squared P = 0.31), significantly more Māori had higher-stage non-seminoma than non-Māori (stage III in 44% and 22%, respectively, chi-squared P = 0.014). Survival for seminoma (logrank P = 0.19) and non-seminoma (logrank P = 0.89) patients did not differ significantly by ethnicity. CONCLUSIONS:Māori patients were younger at diagnosis of testicular cancer and presented with more advanced non-seminoma testicular tumours compared with non-Māori but survival was comparable.

Abstract Purpose: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. Patients and Methods: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Results: A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively. Conclusions: Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.

6039 Background: SD-101, a synthetic CpG-ODN agonist of TLR9, stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in HNSCC. Study DV3-MEL-01 (NCT02521870) assesses safety and efficacy of SD-101 in combination with pembrolizumab in patients with recurrent/metastatic HNSCC. We have previously reported a 27.3% ORR in 22 patients receiving 8 mg SD-101/injection in the modified ITT after at least 2 CT scans due to late responses (Abstract 3560, ESMO 2018). Higher efficacy at a lower SD-101 dose, 2 mg/injection, has been reported in advanced melanoma patients (LBA 45, ESMO 2018). Consequently, this dose is now being assessed in HNSCC. We report preliminary data with the 2 mg/injection dose in 23 patients in mITT at the first CT scan. Methods: Anti-PD-1/PD-L1 naïve patients received 2 mg SD-101 intratumorally in 1 - 4 lesions (weekly x 4 doses then Q3W x 7 doses). Pembrolizumab is was administered IV at 200 mg Q3W. Responses were assessed per RECIST v1.1. Results: 28 patients enrolled: median age 63 y/o, male 68%; ECOG PS 0-1 (18%/82%); mean prior lines of systemic therapy 1 (0-3); mean treatment duration 70 days (1-253). Primary tumors: 19 (68%) oropharyngeal; 3 (10%) laryngeal; 2 (7%) hypopharyngeal; 4 (14%) unknown. Mean number of target lesions: 1.82 (1 to 5). HPV status: 7 (25%) +, 9 (32%) -, 12 (43%) unknown. 18 (64 %) discontinued treatment: 12 (42%) due to PD, 4 (16%) deaths, 1 (3%) consent withdrawn, 1 (3%) went to hospice. Mean follow up 2.70 months. Safety: 16 non-treatment-related SAEs in 9 patients. 2 treatment-related Grade ≥3 AEs: sepsis (4%) and lymphopenia (4% ). No treatment-related deaths. Efficacy: 23 patients in the mITT population with first CT scan at day 64: ORR: CR: 2, PR: 3 (22%); SD: 6 (26%), PD: 7 (30%), non-evaluable: 5 (22%). Disease control rate (48%). 5 patients on study have not had a CT scan. Conclusions: SD-101 with Pembrolizumab shows early promising data and is well tolerated. Additional follow-up scans from both dose cohorts are being evaluated and will be presented. Clinical trial information: NCT02521870.