Phase I Trial of nab-Paclitaxel Administered Concurrently With Radiotherapy in Patients With Locally Advanced Inoperable Pancreatic Adenocarcinoma.

OBJECTIVES: Nab-paclitaxel has radiosensitizing antitumor efficacy in pancreatic cancer. We aimed to establish maximum tolerated dose (MTD) of nab-paclitaxel with radiotherapy in unresectable locally advanced pancreatic cancer. METHODS: In a phase I dose escalation trial patients received weekly nab-paclitaxel for 6 weeks with external beam radiotherapy (EBRT). 3 + 3 design was used with nab-paclitaxel doses: 25 mg/m 2 (cohort 1), 50 mg/m 2 (cohort 2), 75 mg/m 2 (cohort 3), and 100 mg/m 2 (cohort 4). Primary endpoint was MTD. Secondary objectives were progression-free survival and overall survival. RESULTS: Fourteen patients were recruited. Median age was 69 years (range, 40-86). Grade 1/2 toxicities were nausea (93%), vomiting (54%), diarrhea (57%), and fatigue (69%). There were no dose limiting toxicities (DLT) in cohorts 1 to 3. In cohort 4, DLTs of febrile neutropenia and enterocolitis were observed in patient 1. Subsequent DLT of febrile neutropenia and enterocolitis occurred in patient 5 in the expanded cohort. Following chemoradiotherapy median progression-free survival was 4.7 months (95% confidence interval, 2.5-27.5) and median overall survival was 10.8 months (95% confidence interval, 6.37-25.2). CONCLUSIONS: Nab-paclitaxel and EBRT was well-tolerated at doses below 100 mg/m 2 . The MTD and recommended phase II study dose for nab-paclitaxel with EBRT is 75 mg/m 2 in this disease.

Real-world experience of nivolumab in the treatment of poor performance status patients with advanced non-small cell lung cancer.

BACKGROUND: Nivolumab improves disease control and survival in advanced NSCLC in patients with good performance status (PS), but there is limited data on its efficacy in patients with poor PS. AIM: Primary objective of the study was to evaluate the efficacy and safety of nivolumab and examine the influence of PS on outcomes. METHODS AND RESULTS: Retrospective analysis of patients treated with single-agent nivolumab for advanced NSCLC at a single institution was performed. Sixty-six patients treated with nivolumab were identified (33 male) with a median age of 68.5 years. Fifty-six (85%) patients were current or former smokers and 17 (26%) had brain metastasis. All patients had received prior chemotherapy, 39 (59%) patients received one and 27 (41%) had ≥2 prior lines of therapy. Median overall survival (OS) was 7.1 months (95%CI 3.61-11.3) in the overall study population. OS of patients with PS ≥2 at the start of treatment was 3.04 months (95%CI 1.64-7.36) as compared to 10.23 months (95%CI 7.06-18.9) with PS ≤1. The overall response rate was 7% (four patients had a partial response), 23 (40%) patients had stable disease; the overall disease control rate (partial response and stable disease) was 47%. Twenty-six (40%) patients had PS ≥2 at the start of treatment and 2 (8%) of these patients developed a partial response, 4 (15%) had stable disease; the overall disease control rate was 23%. Fourteen (58%) patients with PS ≥2 had disease progression at the time of first disease response evaluation. In the overall population, 20% of patients experienced grade ≥3 treatment-related adverse events (TRAEs), most commonly pneumonitis, hepatitis, and colitis. Fourteen TRAEs led to treatment discontinuation, 9 (23%) adverse events (AEs) in patients with PS ≤1 and 5 (19%) with PS ≥2. Fourteen (21%) patients died within 30 days of the last nivolumab treatment. CONCLUSION: There was no significant difference in toxicity leading to treatment discontinuation between the poor and good PS groups, but survival was shorter with poorer PS. PS appears to be an important prognostic factor and remains a relevant discriminator in the selection of treatment with immunotherapy for lung cancer.

Patterns of care and outcomes for gastric and gastro-oesophageal junction cancer in an Australian population.

BACKGROUND: A single state-wide upper gastrointestinal (GI) cancer video-linked multidisciplinary team (MDT) meeting guides management and evidence-based care for all newly diagnosed upper GI cancer patients in South Australia. This study determined the patterns of care and outcomes for patients diagnosed with gastric and gastro-oesophageal junction (GOJ) cancers. METHODS: Patients diagnosed with gastric cancer and GOJ (Siewert III) cancer between June 2012 and June 2016 were included. Patient demographics, cancer stage, histology, diagnostic modalities and treatment data was analysed from a prospective database. Stage-specific survival outcomes were determined and analysed for each treatment modality. RESULTS: The study included 218 patients and at diagnosis 132 (61%) patients had stage I-III and 86 (39%) patients had stage IV disease. One hundred and ninety-five (89%) patients had gastric cancer and 23 (11%) had GOJ cancer (Siewert III). One hundred and nine (50%) patients underwent surgery, with 92% R0 resection rate. Forty-six patients received perioperative chemotherapy and 111 (51%) patients received palliative intent treatment. Median overall survival for stage II, III and IV cancers was 57.6 (95% CI 57.6-NR), 22.8 (95% CI 20.4-43.2), and 6.0 months (95% CI 4.8-8.4) respectively (p < 0.001). Median overall survival for patients who underwent perioperative chemotherapy and surgery was not reached as compared to 44.4 months (95% CI 28.8-NR) for patients who underwent surgery alone. CONCLUSION: Treatment outcomes for patients with gastric and GOJ cancer managed across South Australia met contemporary evidence-based practice. However, as most patients continue to present with late-stage disease, longer-term survival remains poor.

Sorafenib-related generalized eruptive keratoacanthomas (Grzybowski syndrome): a case report.

BACKGROUND: Sorafenib is an oral multikinase inhibitor that targets Raf serine/threonine receptor tyrosine kinases and inhibits tumor cell growth and angiogenesis. Cutaneous toxicities of sorafenib are common, including cutaneous eruptions (such as truncal erythema and seborrheic-dermatitis-like changes) and hand-foot syndrome. Keratoacanthomas and squamous cell carcinomas have been reported previously; however, we report a case of multiple eruptive keratoacanthomas in the form of Grzybowski syndrome after initiation of sorafenib. CASE PRESENTATION: We report a 63-year-old Caucasian male who developed multiple cutaneous eruptive keratoacanthomas after starting sorafenib 400 mg twice daily. He had a known history of hepatitis-C-related cirrhosis and hepatocellular carcinoma, and previously had actinic keratosis and skin squamous cell carcinoma excision. Approximately two and a half months after starting sorafenib, the patient initially developed two lesions, one on each forearm, and after excision, these lesions demonstrated histological features of squamous cell carcinoma. One month later, the patient presented with approximately 48 new skin lesions of varying size on the back, bilateral upper limbs, and face requiring excisional biopsy of a large number of these lesions. Histopathology showed eruptive invasive keratoacanthomas (Grzybowski syndrome). Sorafenib was temporarily stopped and subsequently restarted at a lower dose. Acitretin 25 mg daily was commenced after few weeks, and no further keratoacanthomas developed during his treatment. CONCLUSIONS: We report a unique case of sorafenib-associated Grzybowski syndrome. Temporary interruption and dose reduction of sorafenib and use of acitretin appeared to prevent further development of keratoacanthomas.

Survival and late toxicities following concurrent chemo-radiotherapy for locally advanced stage III non-small cell lung cancer: findings of a 10-year Australian single centre experience with long term clinical follow up.

BACKGROUND: The preferred management of patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemo-radiotherapy (CRT). Acute CRT-related toxicities are well defined, however, less is known about late toxicities. The aim of the study was to examine the outcomes and late toxicities in Stage III NSCLC treated with CRT. METHODS: A retrospective review of the data from patients with stage III NSCLC treated with CRT was performed between May 2000 and June 2010. Demographics, tumour and treatment characteristics, toxicities and survival data were examined from hospital records of the patients. Progression free survival (PFS) and overall survival (OS) were evaluated by standard Kaplan-Meier survival curves. The censor date was set on 31 October 2016. RESULTS: Sixty-three patients were identified with a median age of 66.6 years [interquartile range (IQR) 57.2-72.1], two-third (n=41, 65.1%) were male, majority were current or ex-smokers (n=52, 82.5%), 42 (66.7%) patients had stage IIIB disease and 21 (33.3%) had stage IIIA disease. The most common histologic subtype was adenocarcinoma 30 (47.6%). The median PFS and OS of the whole population was 10.6 months (95% CI, 4.1-17.3 months) and 21 months (95% CI, 12.7-29.3 months) respectively. The 5-year OS rates for stage IIIA and IIIB were 24% and 16% respectively. The 1-, 3- and 5-year OS rates for all patients were 63.5%, 46% and 18.7% respectively. Acute grade 3 and 4 toxicities included 28 haematological and 17 non-haematological events. The incidence of late toxicities was 58.9%. Thirty-three events of late grade 3 and 4 toxicities were recorded. The most common late toxicity was symptomatic radiation-induced pulmonary fibrosis (39.3%), others include ototoxicity (7.1%), persistent dysphagia (7.1%) and one case of acute myeloid leukaemia. All patients that were alive at the censor date had developed radiation-induced fibrosis with associated symptoms of respiratory insufficiency. CONCLUSIONS: The 5-year OS of patients with stage III NSCLC treated with CRT was in keeping with survival figures reported from prospective clinical trials. There is, however, significant morbidity associated with long-term survival and this should be taken into account when making informed treatment decisions.

Phase I trial of Lipovaxin-MM, a novel dendritic cell-targeted liposomal vaccine for malignant melanoma.

INTRODUCTION: In this phase I study using a 3 + 3 dose escalation design, the safety, dose-limiting toxicity (DLT), immunogenicity and efficacy of intravenous Lipovaxin-MM-a multi-component dendritic cell-targeted liposomal vaccine against metastatic melanoma-was investigated. METHODS: Twelve subjects with metastatic cutaneous melanoma were recruited in three cohorts. Patients in Cohort A (n = 3) and Cohort B (n = 3) received three doses of 0.1 and 1 mL of Lipovaxin-MM, respectively, every 4 weeks. Patients in Cohort C (n = 6) received four doses of 3 mL vaccine weekly. Immunologic assessments of peripheral blood were made at regular intervals and included leukocyte subsets, cytokine levels, and Lipovaxin-MM-specific T-cell and antibody reactivities. Tumor responses were assessed by RECIST v1.0 at screening, then 8 weekly in Cohorts A and B and 6 weekly in Cohort C. RESULTS: Of a total of 94 adverse events (AEs) reported in ten subjects, 43 AEs in six subjects were considered to be possibly or probably vaccine-related. Most (95%) vaccine-related AEs were grade 1 or 2, two (5%) grade 3 vaccine-related AEs of anemia and lethargy were recorded, and higher grade AEs and DLTs were not observed. No consistent evidence of vaccine-specific humoral or cellular immune responses was found in post-immunization blood samples. One patient had a partial response, two patients had stable disease, and the remaining patients had progressive disease. CONCLUSIONS: Lipovaxin-MM was well tolerated and without clinically significant toxicity. Immunogenicity of Lipovaxin-MM was not detected. Partial response and stable disease were observed in one and two patients, respectively.