Immune-related colitis presenting with constipation.

Anticancer immunotherapies modulate the body's immune system to recognise and eradicate cancerous cells. However, stimulation of the body's immune system can also lead to a number of adverse effects when those immune cells target non-cancerous cells in the form of autoimmunity. One relatively common example of this off-target action is colitis.We present three patients who presented atypically with colitis, consequently, leading to a delayed diagnosis. These cases highlight the diverse ways a relatively common immune-related adverse event can present.

A phase Ib study to assess the safety of the human papillomavirus DNA vaccine (AMV002) in combination with durvalumab for HPV-associated oropharyngeal squamous cell carcinoma.

Background: Programmed cell death ligand 1 (PD-L1) inhibitors have limited efficacy as monotherapy in patients with recurrent/metastatic (R/M) Human Papilloma Virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). A phase I study of the therapeutic HPV-16 DNA vaccine AMV002 in curatively treated patients with OPSCC demonstrated a measurable immune response against HPV while being associated with high safety and tolerability. This prospective phase Ib single centre pilot study aims to test the safety and tolerability of combined PD-L1 inhibitor, Durvalumab, with AMV002 in 12 patients with recurrent OPSCC. Methods: Participants had evidence of R/M HPV-associated OPSCC. They received three intradermal administrations of AMV002 with Durvalumab followed by Durvalumab maintenance. Safety and tolerability data was the primary endpoint. The study was conducted with ethical approval (HREC/2018/QMS/47293) in Brisbane, Australia. Findings: The most common adverse event (AE) related to vaccine administration was erythema at the injection site. There were no grade 3 or 4 vaccine related AEs. There was one presumed immune-related grade 3 elevation in lipase secondary to Durvalumab with no intervention required. No patient ceased study due to treatment-related AEs. At week 16, objective response rate was 8% (N=1) and disease control rate was 17% (N=2). At a median follow up of 25.6 (20.0-26.6) months there was one long term complete response while all other participants developed progressive disease. Of the 11 evaluated patients, 9, (82%) had E6 and/or E7-specific T cell responses to the vaccine. Conclusion: The combination of AMV002 therapeutic HPV-16 vaccine and Durvalumab was found to be safe and well tolerated with no increased safety signals generated. T cell responses to vaccine were observed but further work will be required to improve efficacy.

Pembrolizumab Plus Carboplatin and Paclitaxel as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-B10): A Single-Arm Phase IV Trial.

PURPOSE: Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). METHODS: Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m2 on days 1 and 8 or 175 mg/m2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. CONCLUSION: Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.

Management of Recurrent HPV-Positive Oropharyngeal Squamous Cell Carcinoma: a Contemporary Review.

PURPOSE OF REVIEW: To review the impact of contemporary treatment strategies on salvage outcomes in patients with recurrent human papilloma virus-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). RECENT FINDINGS: Secondary to HPV, changes in disease biology have impacted primary treatments and subsequent approaches to patients with recurrence. With treatment strategies more inclusive of upfront surgery, the characteristics of patients with recurrence HPV + OPSCC have been further redefined. Less invasive endoscopic surgical approaches such as transoral robotic surgery (TORS), and the continued refinement of conformal radiotherapy techniques, have improved treatment options for patients with recurrent HPV + OPSCC. Systemic treatment options have continued to expand including potentially effective immune-based therapies. Effective surveillance with systemic and oral biomarkers offers hope of earlier detection of recurrence. Management of patients with recurrent OPSCC remains difficult. Modest improvements in salvage treatment have been observed within the HPV + OPSCC cohort largely reflecting disease biology and improved treatment techniques.

Toxicity and response to ipilimumab and nivolumab in older patients with metastatic melanoma: A multicentre retrospective analysis.

Combination immunotherapy with nivolumab and ipilimumab is an effective therapy in the treatment of metastatic melanoma, however, its benefit in older patients is unclear. A multicentre retrospective study was performed to compare the efficacy and toxicity of combination immunotherapy in metastatic melanoma in patients ≥65 years versus <65 years, and complications of steroids used to manage toxicity. One hundred and thirty-nine patients were included with 52 patients ≥65 years (median age: 70; range: 65-83) and 87 patients <65 years (median age: 52; range: 22-64). Median overall survival was similar in patients ≥65 years versus <65 years (14.9 vs. 17.3 months p = .58). Median progression-free survival was also similar in both groups (7.1 vs. 6.9 months p = .79), as was overall response rate (48.1% vs. 44.8% p = .73). Age was not associated with a difference in overall survival on multivariate analysis. There was similar rates of Grade 3 or higher adverse events in patients ≥65 years versus <65 years (50% vs. 49% p = 1.0) and discontinuation rates secondary to toxicity (55.8% vs. 56% p = 1.0). Median duration of steroids used to treat adverse events was similar (11 vs. 12 weeks p = .46). Complications of steroids requiring inpatient admission was numerically higher in the older patients (41.3% vs. 20.4% p = .07). Patients ≥65 years received similar benefit from combination immunotherapy in comparison to their younger counterparts with similar toxicity.

Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial.

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Safety and efficacy of telephone clinics during the COVID-19 pandemic in the provision of care for patients with cancer.

BACKGROUND: Due to the COVID-19 pandemic, telephone clinics have been utilised to reduce the risk of transmission. Evidence supporting its quality and safety is required. AIMS: Assess the efficacy and safety of telephone clinics in delivering care to established oncology patients and assess patient and health professionals' preference (telephone vs face-to-face clinics). METHODS: Retrospective chart audit in the month preceding and month following the introduction of telephone clinics at the Gold Coast University Hospital and a patient and health professional questionnaire. RESULTS: In total, 1212 clinical encounters occurred in the month post the introduction of telephone clinics (vs 1208 encounters prior). There were no statistically significant differences in 24-h (18 vs 22, P = 0.531) or 7-day admissions (50 vs 46, P = 0.665) comparing encounters in the month prior to the introduction of telephone clinics versus the month post, but there was a statistically significant difference in 30-day mortality post systemic therapy in favour of the post-telephone clinic period (7 vs 0 patients, P = 0.008). Of the 222 patients who undertook the questionnaire, 42.3% preferred telephone clinics (95% confidence interval (CI) 35.97-48.97), 25.2% preferred face-to-face clinics (95% CI 19.92-31.39) and 32.4% did not prefer one method over another. Of the 24 health professionals who undertook the questionnaire, 70.8% felt patients preferred phone clinics. CONCLUSIONS: Generally, patients and clinicians viewed telephone clinics favourably. Nevertheless, a large portion of patients still prefer face-to-face clinics. Services should be tailored to individual preferences. Although there were no 'red flags' in terms of mortality or admission rates, further longitudinal research is required.

Complete clinical response of a neglected cutaneous melanoma with combined radiotherapy and immunotherapy: A case report.

The treatment of patients with advanced melanoma has undergone a dramatic change over the past decade. Apart from refining the radiotherapy techniques, the repertoire of systemic treatments expanded from largely futile cytotoxic chemotherapy to substantially more effective MAP kinase and immune checkpoint inhibitors (Immunotargets Ther, 7, 2018)1 . We report a case which exemplifies the improved efficacy as well as increased complexity of therapeutic decision-making. A 71-year-old man presented with neglected fungating and bleeding malignant melanoma, which resulted in severe anaemia with consequent cardiac dysfunction. There was limited distant spread. Patient was treated with combined radiotherapy and immunotherapy: 55 Gray in 20 fractions over four weeks using 3D-conformal technique followed by an anti-PD1 antibody (pembrolizumab, Keytruda® Merck/MSD, Kenilworth N.J.; 2 mg/kg 3-weekly). A surgical approach to provide haemostasis and cosmesis was considered, but would be associated with significant morbidity, prolonged recovery and functional impairment and would not have altered patient survival. The sequential radioimmunotherapy resulted in a complete response. Radiotherapy was completed with only mild skin toxicity. Immunotherapy was complicated by diarrhoea, which necessitated withdrawal of the medication but was controlled with steroids. The non-operative treatment resulted in excellent oncological, functional and cosmetic outcome, with acceptable toxicity. Due to increasing complexity of melanoma therapy, a multidisciplinary approach is of paramount importance.

Cetuximab associated dermal filler reaction.

A 52-year-old male patient with hyaluronic acid-based dermal fillers injected in his cheeks was diagnosed with glossotonsillary malignancy, and managed with concurrent cetuximab (epidermal growth factor receptor inhibitor) and radiation therapy. He developed significant inflammation around the dermal filler sites after first cycle of cetuximab which improved with dissolution of the dermal fillers with hyaluronidase. This suggests that cetuximab can lead to inflammation around the dermal filler sites, which can be treated with dissolution of the filler.

Radiotherapy utilization in BRAF mutation-tested metastatic melanoma in the targeted therapy era.

AIM: Tumor BRAF mutation testing is routine for all patients with metastatic melanoma (MM) owing to the availability of agents targeting this intracellular pathway. To test whether there is a difference in radiotherapy (RT) utilization according to BRAF mutation status, we performed a retrospective review of RT utilization in a contemporary cohort undergoing BRAF mutation testing. METHODS: Clinical records of MM patients undergoing BRAF mutation testing between April 2010 and August 2012 were reviewed. Overall survival (OS) was calculated using Kaplan-Meier methods. Differences between BRAF status were calculated using chi-square tests for categorical variables, median tests for continuous variables and Cox proportional hazards models to compare OS. RESULTS: Up to 158 patients were identified but 17 were excluded due to inadequate clinical data. Of the remaining 141 patients, 69 (49%) tested BRAF mutant (BRAF-m), median age 47 years (range 21-79) with median follow-up of 16.8 months (IQR11.3-25.2). Seventy-two (51%) tested BRAF wild type (BRAF-w), median age 62 years (range 25-84) with median follow-up of 27.1 months (IQR12.5-57.4). Overall, RT utilization was similar: 68% in BRAF-m and 69% in BRAF-w. Mean number of treatment courses was 1.70 for BRAF-m and 2.36 for BRAF-w (Pearson chi-square 3.92, P = 0.05). Up to 51% of BRAF-m and 56% of BRAF-w required ≧2 RT courses. Forty-six percent BRAF-m compared with 29% BRAF-w received brain RT (P = 0.04). Median OS was 17.7 months (IQR7.6-35.5) in BRAF-m and 19 months (IQR7.8-35.1) in BRAF-w (P = 0.99). CONCLUSION: High RT utilization rates were observed irrespective of BRAF mutation status. Significantly more BRAF-w patients received RT but more BRAF-m patients received brain RT.

RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma.

We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient samples. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7-dependent upregulation of RacGAP1 in doxorubicin-insensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that overexpress RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin.

A novel E2F/sphingosine kinase 1 axis regulates anthracycline response in squamous cell carcinoma.

PURPOSE: Head and neck squamous cell carcinomas (HNSCC) are frequently drug resistant and have a mortality rate of 45%. We have previously shown that E2F7 may contribute to drug resistance in SCC cells. However, the mechanism and pathways involved remain unknown. EXPERIMENTAL DESIGN: We used transcriptomic profiling to identify candidate pathways that may contribute to E2F7-dependent resistance to anthracyclines. We then manipulated the activity/expression of the candidate pathway using overexpression, knockdown, and pharmacological inhibitors in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and a downstream effector in a tissue microarray (TMA) generated from HNSCC patient samples. RESULTS: E2F7-deficient keratinocytes were selectively sensitive to doxorubicin and this was reversed by overexpressing E2F7. Transcriptomic profiling identified Sphingosine kinase 1 (Sphk1) as a potential mediator of E2F7-dependent drug resistance. Knockdown and overexpression studies revealed that Sphk1 was a downstream target of E2F7. TMA studies showed that E2F7 overexpression correlated with Sphk1 overexpression in human HNSCC. Moreover, inhibition of Sphk1 by shRNA or the Sphk1-specific inhibitor, SK1-I (BML-EI411), enhanced the sensitivity of SCC cells to doxorubicin in vitro and in vivo. Furthermore, E2F7-induced doxorubicin resistance was mediated via Sphk1-dependent activation of AKT in vitro and in vivo. CONCLUSION: We identify a novel drugable pathway in which E2F7 directly increases the transcription and activity of the Sphk1/S1P axis resulting in activation of AKT and subsequent drug resistance. Collectively, this novel combinatorial therapy can potentially be trialed in humans using existing agents.

Response rate to vemurafenib in patients with B-RAF-positive melanoma brain metastases: a retrospective review.

The intracerebral response rate (RR) to vemurafenib in patients with B-RAF mutated melanoma brain metastasis was assessed. Patients with B-RAF-positive metastatic melanoma and asymptomatic brain metastases at initiation of vemurafenib were eligible. Records were analysed retrospectively to calculate the RR, duration of responses, time to central nervous system (CNS) progression and overall survival. Twenty-two patients with CNS metastasis received vemurafenib (male : female=13 : 9; median age 49); 12 had received no previous local therapy to the brain (group A), six had undergone previous surgery and/or radiotherapy with residual disease (group B; n=6) and four patients had received previous local therapy to the brain but with evidence of progression in the CNS before the start of vemurafenib and were included in group A (n=12+4=16). A 50% RR was observed in group A. Duration of responses was between 8 and 32 weeks. Similarly, a 50% RR was observed in group B; however, the contribution of vemurafenib to CNS control in this group was more difficult to assess. The duration of responses in group B was 4-33 weeks. All except two patients progressed in CNS before, or at the time of, systemic progression. The median time to CNS progression for the entire cohort was 23 weeks (range 12-60) in responding patients and 14 weeks (3-22) in those without a response. The median overall survival was 46 weeks for the patients with an objective response and 21 weeks among the nonresponding patients. Vemurafenib resulted in a 50% CNS RR. A prospective assessment of the medication in patients with B-RAF mutated melanoma cerebral metastases is warranted.