Outcomes of patients with gallbladder cancer presenting with acute cholecystitis.

The main purpose of this study is to explore the outcomes of patients found to have gallbladder cancer during investigation and diagnosis of acute cholecystitis. The incidence of primary gallbladder cancer co-existing in acute cholecystitis is not well defined in the literature, with anecdotal reports suggesting that they experience worse outcomes than patients with gallbladder cancer found incidentally. METHODS: A retrospective review of all patients with gallbladder cancer managed at the Canberra Health Service between 1998 and May 2022 were identified and reviewed. RESULTS: A total of 65 patients were diagnosed with primary gallbladder cancer during the study period with a mean age of 70.4 years (SD 11.4, range 59-81.8 years) and a female preponderance (74% versus 26%) with a ratio of 2.8. Twenty (31%) patients presented with acute calculus cholecystitis and were found to have a primary gallbladder cancer. This group of patients were older and predominantly female, but the difference was not statistically significant. The overall 5-year survival in the cohort was 20% (stage 1 63%, stage 2 23%, stage 3 16%, and stage 4 0%). There was no statistically significant difference in survival between those who presented with acute cholecystitis vs other presentations. CONCLUSIONS: A third of the patients with gallbladder cancer presented with acute cholecystitis. There was no statistically significant difference in survival in those with bile spillage during cholecystectomy as well those presenting with acute cholecystitis.

The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer.

BACKGROUND: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy. METHODS: Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15. RESULTS: Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months. CONCLUSIONS: The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.

Accuracy and Prognostic Significance of Oncologists' Estimates and Scenarios for Survival Time in Advanced Gastric Cancer.

BACKGROUND: Worst-case, typical, and best-case scenarios for survival, based on simple multiples of an individual's expected survival time (EST), estimated by their oncologist, are a useful way of formulating and explaining prognosis. We aimed to determine the accuracy and prognostic significance of oncologists' estimates of EST, and the accuracy of the resulting scenarios for survival time, in advanced gastric cancer. MATERIALS AND METHODS: Sixty-six oncologists estimated the EST at baseline for each of the 152 participants they enrolled in the INTEGRATE trial. We hypothesized that oncologists' estimates of EST would be unbiased (∼50% would be longer or shorter than the observed survival time [OST]); imprecise (<33% within 0.67-1.33 times the OST); independently predictive of overall survival (OS); and accurate at deriving scenarios for survival time with approximately 10% of patients dying within a quarter of their EST (worst-case scenario), 50% living within half to double their EST (typical scenario), and 10% living three or more times their EST (best-case scenario). RESULTS: Oncologists' estimates of EST were unbiased (45% were shorter than the OST, 55% were longer); imprecise (29% were within 0.67-1.33 times observed); moderately discriminative (Harrell's C-statistic 0.62, p = .001); and an independently significant predictor of OS (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; p = .001) in a Cox model including performance status, number of metastatic sites, neutrophil-to-lymphocyte ratio ≥3, treatment group, age, and health-related quality of life (EORTC-QLQC30 physical function score). Scenarios for survival time derived from oncologists' estimates were remarkably accurate: 9% of patients died within a quarter of their EST, 57% lived within half to double their EST, and 12% lived three times their EST or longer. CONCLUSION: Oncologists' estimates of EST were unbiased, imprecise, moderately discriminative, and independently significant predictors of OS. Simple multiples of the EST accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer. IMPLICATIONS FOR PRACTICE: Results of this study demonstrate that oncologists' estimates of expected survival time for their patients with advanced gastric cancer were unbiased, imprecise, moderately discriminative, and independently significant predictors of overall survival. Simple multiples of the expected survival time accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer.

The survival outcome of patients with metastatic colorectal cancer based on the site of metastases and the impact of molecular markers and site of primary cancer on metastatic pattern.

BACKGROUND: Pattern of spread in patients with metastatic colorectal cancer (mCRC) is variable and may reflect different biology in subsets of patients. This is a retrospective study to explore the outcome of patients with mCRC based on their site of metastasis at diagnosis and to explore the association between tumor characteristics [KRAS/RAS, BRAF, mismatch repair (MMR) status, site of primary] and the site of metastasis. METHODS: Patients from two Australian databases were divided into six groups based on site of metastasis at time of diagnosis of metastatic disease; lung-only, liver-only, lymph node-only or any patients with brain, bone or peritoneal metastases. Primary endpoint was overall survival (OS) of each cohort compared with the rest of the population. A Mantel-Haenszel chi-squared test used to explore the association between site of metastasis and selected tumor characteristics. RESULTS: Five thousand nine hundred and sixty-seven patients were included. In a univariate analysis, median OS was significantly higher when metastases were limited to lung or liver and shorter for those with brain, bone or peritoneal metastases (p < .001) in both datasets. BRAF mutation was strongly associated with peritoneal metastases (relative risk = 1.8, p < .001) with lower incidence of lung (RR = 0.3, p = .004) and liver (RR = 0.7, p = .005) limited metastases. Lung-only metastases were more frequent with KRAS/RAS mutation (RR = 1.4, p = .007). Left colon tumors were associated with bone (RR = 1.6, p < .001) and lung-only metastases (RR = 2.3, p = .001) while peritoneal spread was less frequent compared with right colon tumors (RR = 0.6, p < .001). Rectal cancer was associated with brain, bone and lung metastases (RR = 1.7; p = .002, 1.7; p < .001, 2.0; p < .001). Liver-only metastases were less frequent in deficient MMR tumors (RR = 0.7, p = .01). CONCLUSION: Survival duration with mCRC is related to the site of metastases with lung limited disease showing a more favorable survival outcome compared to other single metastatic site disease. The BRAF mutation and primary rectal cancer were associated with poor prognostic metastatic sites.

European-Australasian consensus on the management of advanced gastric and gastro-oesophageal junction cancer: current practice and new directions.

Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2-targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making.

Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial.

BACKGROUND: Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population. METHODS: Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47-67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051. FINDINGS: 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59-77) and 83% (76-91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65-83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism). INTERPRETATION: Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted. FUNDING: UK National Health Service, Sanofi-Aventis.

Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.

BACKGROUND: A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. METHODS: We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. RESULTS: ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). CONCLUSIONS: In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971 [controlled-trials.com].).

Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker.

The human epidermal growth factor receptor (HER1/EGFR/ErbB1) signaling is aberrant and overexpressed in many solid malignancies making it an appealing target for biologic agents. Among the classes of drugs targeting EGFR are monoclonal antibodies and EGFR tyrosine kinase inhibitors, which have been shown effective and generally well tolerated in different clinical settings. The majority of patients treated with EGFR inhibitors (EGFRIs) develop specific dose-dependent skin toxicity. This side effect may lead to physical and psychosocial discomfort which can result in dose reduction or treatment interruption. The relationship between rash and clinical outcome has stimulated interest in this particular toxicity as a possible surrogate marker of efficacy in patients treated with targeted agents against EGFR. This review aims to summarize and update the current knowledge of the clinical presentation, predictive and prognostic value, and the management of EGFRI-related skin toxicity.

Pharmacotherapy for oesophagogastric cancer.

Gastric cancer is the seventh and oesophageal cancer the ninth most common cancer in the UK, and >50% of patients present with locally advanced or metastatic disease. The incidence of oesophageal and oesophagogastric junctional tumours is increasing, making these important disease entities to understand and research. Despite improvements in surgical and peri-operative supportive care, 3-year overall survival with surgery alone for resectable disease is still poor. Outcomes in localised oesophageal cancer are improved with pre-operative chemotherapy, and in gastric cancer with peri-operative treatment or post-operative chemoradiotherapy. Oesophageal squamous cell carcinoma can be treated with definitive chemoradiotherapy as an alternative to surgery. While survival in patients presenting with metastatic disease is improved with the addition of systemic chemotherapy, median survival remains <1 year. Patients who are otherwise fit can be offered chemotherapy and this is superior to best supportive care. Regimens including a platinum and an anthracycline agent are favoured by the results of randomised trials. No standard second-line therapy has emerged. New research into taxanes has shown promising anti-cancer activity, and novel areas of investigation include incorporation of agents targeting vascular endothelial growth factor or epidermal growth factor receptor into standard regimens. This review focuses on the clinical trial evidence that dictates the optimal management of localised and advanced oesophagogastric cancer, focusing on pharmacotherapy. We examine areas of current research and highlight future therapeutic directions.

Current treatment strategies in elderly patients with metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in the Western world, with > 500,000 new cases diagnosed each year. One of the strongest risk factors for colon cancer is age. The incidence rates rise from 10 in 100,000 at age 40-45 years to 300 in 100,000 at age 75-80 years, with the median age at diagnosis of CRC being 71 years. With the general demographic shift toward an aging population, the number of people aged > 65 years is expected to increase. This article reviews the development of treatment for elderly patients with metastatic CRC, from single-agent fluoropyrimidines to combination therapies.

Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer?

The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted.

Adjuvant treatment for resectable pancreatic cancer.

There are relatively few randomized studies of adjuvant chemoradiotherapy and chemotherapy in patients with resected pancreatic adenocarcinoma. The European Study Group for Pancreatic Cancer 1 (ESPAC1) trial is the largest study of adjuvant treatment to date. The results of ESPAC1 are discussed in the context of other evidence from previous randomized studies, which have also been combined in a meta-analysis. Overall, the existing data show a clear benefit for postoperative adjuvant chemotherapy, which has not been demonstrated for adjuvant chemoradiotherapy. The subgroup of patients with resection margin positive disease did seem to benefit less from adjuvant chemotherapy, and showed a trend towards improved survival with chemoradiotherapy. Adjuvant chemoradiotherapy should be evaluated further in this latter group of patients. The optimal chemotherapy regimen for use as adjuvant treatment is the subject of ongoing trials. Other strategies which should be explored include neoadjuvant treatment and the incorporation of novel targeted agents into management.

Chemotherapy for advanced pancreatic cancer.

Single-agent gemcitabine was established as standard treatment for advanced pancreatic cancer after a superior clinical benefit response was demonstrated in a randomized study comparing it to 5-fluorouracil (FU). Until recently, many subsequent randomized trials of newer, often gemcitabine-based combinations have not been able to show improved survival over gemcitabine. Combination gemcitabine and capecitabine is likely to become the preferred standard treatment, at least in the UK, on the basis of the positive interim results of the UK National Cancer Research Institute (NCRI) randomized study of chemotherapy with this combination. At present, there is no standard second-line treatment for patients who have become refractory to gemcitabine, although a recently reported study has suggested that oxaliplatin with FU and leucovorin is superior to best supportive care in these patients. This article will review and discuss the clinical trials of chemotherapy for this disease, including the more recent trials, which have included the novel targeted agents.

Neoadjuvant treatment of unresectable liver metastases from colorectal cancer.

There has been increasing interest in the use of neoadjuvant treatment for downstaging and downsizing disease in patients with initially unresectable liver metastases from colorectal cancer with a view to potentially curative surgery. This has been increasingly feasible with the more active treatment combinations presently available based on oxaliplatin or irinotecan. This article reviews the evidence supporting the use of this treatment strategy and discusses the implications of advances in treatment in other metastatic disease settings for these patients and the issues of patient selection and prognostic factors.

Single institutional series of neuroendocrine tumors managed in the Australian Capital Territory.

AIMS: Retrospective review of neuroendocrine tumors (NETs) treated within the Australian Capital Territory to describe the local epidemiology and assess prognostic clinicopathological factors. METHODS: Patients with histologically proven non-pulmonary low to intermediate grade NETs were identified from our hospital clinical database. Data were analyzed according to epidemiological, clinical and histopathological characteristics. RESULTS: Of the 107 included patients, the most common primary tumor site was jejunum/ileum (32%), followed by rectum (22%) and pancreas (11.2%). In total, 32% had distant metastases at presentation, most commonly in the liver. Most patients were symptomatic at diagnosis, while 22.4% of cases were found incidentally. Second malignancies, in particular of gastrointestinal origin, were diagnosed in 33.6%. Surgical debulking was the most common treatment (59.8%) while 18% had multimodality therapy. With a median follow-up of 25 months from diagnosis, about 78% of patients are still alive. Median time to first relapse was 15 months and the 5-year survival rate was 80% for NETs of jejunum/ileum. Univariate survival analysis revealed tumor location, high Ki67 index, raised plasma chromogranin A, and urine 5-hydroxyindoleacetic acid upon diagnosis to be associated with shorter 5-year survival. CONCLUSION: The epidemiologic characteristics and long-term outcome in our series are comparable to other reported studies. This analysis presents some important prognostic factors which could be used for risk stratification in patients with NETs.

Recent data with anti-epidermal growth factor receptor antibodies and irinotecan in colon cancer.

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of colorectal cancers. It is the target for a class of agents at the forefront of development for the treatment of colorectal cancer, ie, the anti-EGFR monoclonal antibodies, which include cetuximab, panitumumab, and matuzumab. At present, cetuximab is the furthest along in terms of established efficacy in the treatment of metastatic or inoperable disease and is licensed for the treatment of patients with irinotecan-refractory colorectal cancer. This article reviews the recent evidence supporting the combination of these anti-EGFR agents with the cytotoxic chemotherapeutic agent irinotecan.

Recent advances in management of small-cell lung cancer.

Small-cell lung cancer (SCLC) is a smoking-related disease with a poor prognosis. While SCLC is usually initially sensitive to chemotherapy and radiotherapy, responses are rarely long lasting. Frustratingly, most patients ultimately relapse, often with increasingly treatment resistant disease. Many strategies have been developed in an attempt to improve treatment outcomes, which have plateaued since the introduction of combination chemotherapy in the 1980s. These include trials of maintenance therapy, and dose intensification, the latter by means of increasing dose density, growth factor support and high dose chemotherapy with autologous stem cell rescue. None have been shown to improve patient survival. On the other hand, the integration of concurrent thoracic radiation and prophylactic cranial irradiation has improved the survival outcomes in patients with limited disease. In extensive disease, irinotecan combined with cisplatin has shown promise in improving survival over conventional platinum/etoposide chemotherapy schedules and a confirmatory study is awaited. The future of SCLC treatment may however lie with molecularly targeted therapies, such as antiangiogenesis agents and signal transduction inhibitors, which are being studied at present.