Vy Broadbridge

Cetuximab in metastatic colorectal cancer.

Management of metastatic colorectal cancer has evolved in the last 10 years, with the availability of targeted therapies resulting in improvement in quality of life and overall survival. Cetuximab is a chimeric monoclonal antibody that binds to the EGF receptor, and the net effects are inhibition of tumor growth, invasion, angiogenesis and metastasis. Cetuximab binding to the EGF receptor is also known to augment the effects of chemotherapy and radiotherapy. Only tumors expressing wild-type KRAS respond to cetuximab and improvements in progression-free survival and overall survival are seen, whereas patients with mutant KRAS are considered to be resistant. Cetuximab is currently available worldwide for use as monotherapy or in combination with chemotherapy in first-, second- or third-line settings in metastatic colorectal cancer patients with wild-type KRAS.

Rechallenge with oxaliplatin and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy

Objectives:Patients with advanced colorectal cancer (CRC) who have received oxaliplatin, 5-fluoropyrimidine, and irinotecan chemotherapy (with or without bevacizumab) and antiepidermal growth factor receptor therapy (if KRAS is wild type) have no further standard treatment options. Although repeating a prior chemotherapy [in particular, oxaliplatin and fluoropyrimidine (FOX)] is an option, there is very little evidence in the literature for this approach; thus, we reviewed our registry to assess the frequency and outcome of rechallenging with FOX. Methods:Patients who had been rechallenged with FOX were identified from the South Australian metastatic CRC database. Patient characteristics were analyzed, and tumor response was retrospectively assessed using Response Evaluation Criteria in Solid Tumors criteria. Results:Twenty patients were eligible for inclusion in this analysis. The number of prior lines of therapy received for metastatic CRC was 4 lines for 2 patients, 3 lines for 6 patients, 2 lines for 7 patients, and 1 line for 3 patients, with 3 patients having received oxaliplatin as adjuvant therapy. Four patients had received bevacizumab previously, 7 patients had undergone antiepidermal growth factor receptor treatment, and 4 patients had undergone liver resection earlier. Response rate was 18%, and 47% had stable disease. The median progression-free survival was 3.7 months, median overall survival was 7.8 months, and 1-year survival was 37%. Conclusions:In this selected population, there is evidence of modest activity of rechallenge with FOX chemotherapy, although radiologic response is uncommon.

Do metastatic colorectal cancer patients who present with late relapse after curative surgery have a better survival

Background:Patients who relapse after potentially curative surgery for colorectal cancer tend to relapse within 5 years. There is, however, a group of patients who relapse beyond 5 years after resection and this late relapsing group may have a different behaviour and prognosis.Methods:We analysed data from a prospective population-based registry to compare the characteristics and survival of relapsed patients with metachronous mCRC. Patients were categorised into relapse at <2, 2–5 and >5 years following their initial surgery. Univariate log-rank tests and multivariate Cox regression was performed to determine whether time to relapse (TTR) and other factors were associated with overall survival (OS).Results:A total of 750 metachronous mCRC patients were identified. In all, 56% relapsed ⩽2 years, 32.4% at 2–5 years and 11.6% >5 years. Median survival time from the time of diagnosis of mCRC for the three groups was 17.6, 26.1 and 27.5 months, respectively. Short TTR (<2 years) was significantly associated with survival (HR=0.75, 95% confidence interval (CI)=0.60–0.93 and HR=0.73, 95% CI=0.53–1.01, respectively, for 2–5 and >5 years vs <2 years, P<0.05). However, there was no significant difference in survival between patients who relapsed at 5 years or later compared with those who relapsed between 2 and 5 years (HR=0.98, 95% CI=0.69–1.38, P=0.90).Conclusion:TTR within 2 years is an independent predictor of shorter survival time for mCRC patients who experience a relapse. These data do not support the hypothesis that patients who have late relapse late (>5 years) have a ‘better’ biology or survival compared with patients with a TTR of 2–5 years.

A phase I study to determine the safety, tolerability and maximum tolerated dose of green-lipped mussel (Perna canaliculus) lipid extract, in patients with advanced prostate and breast cancer

BACKGROUND This was a phase I trial to determine the maximum tolerated dose (MTD) of a marine lipid extract from the New Zealand green-lipped mussel (Perna canaliculus), as an inhibitor of 5- and 12-lipo-oxygenase enzymes, in patients with advanced breast and prostate cancers. PATIENTS AND METHODS This was an open-labelled, phase I, dose-escalation study. Proprietary form of green-lipped mussel lipid extract (GLMLE), 260-mg capsule, was administered on a twice-daily schedule, orally. Patients remained on study until disease progression or unacceptable toxicity. RESULTS From December 1999 to May 2003, 17 patients were enrolled. Fifteen of them were male with advanced prostate cancer and two were female with advanced breast cancer. The median age of the patients was 74 years (range 56-85 years). Sixteen patients were assessable for adverse events and dose-limiting toxicity (DLT). Reason for withdrawal from the study included progressive disease (n = 12), death (n = 1) and DLT (n = 3). Two patients had evidence of grade 4 hepatic dysfunction. The MTD was not reached. There were no objective tumour responses noted. CONCLUSIONS GLMLE appears to be a well-tolerated compound in this setting. There appears to be no objective benefit. However, grade 3/4 hepatic toxicity noted in two patients is of concern and should be considered while evaluating patients taking GLMLE or while designing studies with this agent.

Can we accurately report PTEN status in advanced colorectal cancer

BackgroundLoss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results.MethodsWe assessed loss of PTEN function in 51 colorectal cancer specimens using Taqman® copy number variation (CNV) and IHC. Two blinded pathologists performed independent IHC assessment on each specimen and inter-observer variability of IHC assessment and concordance of IHC versus Taqman® CNV was assessed.ResultsConcordance between pathologists (PTEN loss vs no loss) on IHC assessment was 37/51 (73%). In specimens with concordant IHC assessment, concordance between IHC and Taqman® copy number in PTEN loss assessment was 25/37 (68%).ConclusionAssessment PTEN loss in colorectal cancer is limited by the inter-observer variability of IHC, and discordance of CNV with loss of protein expression. An understanding of the genetic mechanisms of PTEN loss and implementation of improved and standardized methodologies of PTEN assessment are required to clarify the role of PTEN as a biomarker in colorectal cancer.

Equivalence of outcomes for rural and metropolitan patients with metastatic colorectal cancer in South Australia

Objective: To compare the management and outcome of rural and metropolitan patients with metastatic colorectal cancer (mCRC) in South Australia.

Reversing Hyperammonemia in Neuroendocrine Tumors.

Ammonia is a neurotoxin that is normally cleared by the intact liver and if not, hyperammonemia results in hepatic encephalopathy. Hyperammonemia may be owing to primary or secondary causes. Early diagnosis is important to prevent permanent brain damage. Advanced malignancy involving the liver is associated with hyperammonemia as a result of abnormality of the portal venous system or massive hepatic tumor burdon. Neuroendocrine tumors are an example of a malignant process that frequently involves the liver but despite this, may still have a relatively good prognosis, and are often characterized by chronic manageable symptoms and slow progression. Hyperammonemia in neuroendocrine tumor would represent a potentially reversible but ongoing process associated with an indolent malignancy. We present 2 cases that are examples of this diagnosis and discuss the diagnostic and management issues that may arise.

Contrast induced hyperthyroidism due to iodine excess

Iodine induced hyperthyroidism is a thyrotoxic condition caused by exposure to excessive iodine. Historically this type of hyperthyroidism has been described in areas of iodine deficiency. With advances in medicine, iodine induced hyperthyroidism has been observed following the use of drugs containing iodine—for example, amiodarone, and contrast agents used in radiological imaging. In elderly patients it is frequently difficult to diagnose and control contrast related hyperthyroidism, as most of these patients do not always present with typical signs and symptoms of hyperthyroidism. Treatment can be very challenging as drugs commonly used to treat hyperthyroidism have little effect on already formed thyroid hormone due to iodine excess.

Pancreatic, periampullary and biliary cancer with liver metastases: Should we consider resection in selected cases?

AIM To analyse the safety and efficacy of curative intent surgery in biliary and pancreatic cancer. METHODS An extensive literature review was performed using MEDLINE, Google Scholar and EMBASE to identify articles regarding hepato-pancreatoduodenectomy or resection of liver metastasis in patients with pancreatic, biliary tract, periampullary and gallbladder cancers. RESULTS A total of 19 studies were identified and reviewed. Major hepatectomy was undertaken in 391 patients. The median overall survival for pancreatic cancer ranged from 5-36 mo and for biliary tract/gallbladder cancer, it was 8-38 mo. The 30 d mortality rate was only 1%-9%. Overall Survival was significantly better for patients, who had good response to neoadjuvant chemotherapy, underwent metachronous liver resection and who had intestinal type tumours. CONCLUSION Resection of liver metastases in pancreatic and biliary cancers may provide survival benefit without compromising safety and quality of life in a very select group of patients. These data may be utilised to formulate selection criteria that may allow future investigation of resection in the era of more effective systemic therapy.