Nimit Singhal

Response to erlotinib in a patient with treatment refractory chordoma

Chordomas are rare tumors arising from the axial skeleton. The disease is characterized by slow local growth, frequent local recurrences, and rare systemic spread. Surgery and local radiation remains the mainstay of treatment with minimal role of systemic therapy. Imatinib has been shown to be active in a phase II trial with symptomatic and radiological responses. We report a case where treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, induced symptomatic and radiological response in a patient with disease refractory to imatinib and vascular disrupting agent.

Prolonged and severe myelosuppression in two patients after low-dose temozolomide treatment- case study and review of literature.

Temozolomide is an alkylating agent used frequently in the management of gliomas. Although temozolomide is generally safe, rarely it can cause life threatening complications. Here we report the cases of two patients who developed prolonged and severe pancytopenia after low dose continuous temozolomide concurrently with cranial radiotherapy. The pancytopenia lasted two to six months. Both the patients were young, treatment naïve, and had temozolomide treatment for only approximately four weeks.

Potentially inappropriate medication use in older people with cancer: Prevalence and correlates

OBJECTIVES Potentially inappropriate medication (PIM) use has been associated with an increase in adverse drug events, hospitalization and mortality. This study investigated the prevalence and factors associated with PIM use in patients presenting to a medical oncology outpatient clinic. MATERIALS AND METHODS Consecutive patients (n=385) aged ≥ 70 years referred to a medical oncology outpatient clinic between January 2009 and July 2010 completed a structured data collection instrument. The instrument assessed medication use, diagnoses, self-reported falls in the previous six months, pain (10-point visual analog scale [VAS]) and distress (10-point VAS). Frailty was defined using exhaustion, weight loss, Karnofsky Performance Scale, instrumental activities of daily living and physical function. PIM use was defined by the Beers Criteria. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with PIM use. RESULTS In total, 26.5% (n=102) of the sample used ≥1 PIM. The five most prevalent classes of PIMs were benzodiazepines (n=34, 8.8%), tricyclic antidepressants (n=16, 4.2%), alpha-adrenoreceptor antagonists (prazosin) (n=15, 3.9%), propulsives (metoclopramide) (n=15, 3.9%) and non-steroidal anti-inflammatory drugs (n=14, 3.6%). In multivariate analyses, PIM use was associated with age 75-79 years (OR 1.83; 95%CI 1.02-3.26) compared to age 70-74 years, using ≥ 5 medications (OR 4.10; 95%CI 2.26-7.44) compared to <5 medications and being frail (OR 3.05; 95%CI 1.18-7.87) compared to being robust. CONCLUSION More than one quarter of older people with cancer used one or more PIMs, and this was associated with being frail compared to being robust.

Eosinophilic fasciitis as a paraneoplastic phenomenon associated with metastatic colorectal carcinoma.

A 72‐year‐old man presented with erythema and induration of his calves and forearms. He had a past history of stage 1 colorectal carcinoma, treated with resection and primary anastamosis 4 years earlier. A diagnosis of eosinophilic fasciitis was made based on the characteristic clinical appearance, peripheral blood eosinophilia and a skin biopsy. There was no improvement in the condition following treatment with prednisolone or methotrexate. One year later, abnormal liver function studies were noted, and an abdominal computed tomography scan and subsequent needle biopsy of the liver confirmed a neoplastic lesion in the liver consistent with a metastatic colorectal carcinoma. Systemic chemotherapy with oxaliplatin, 5‐fluorouracil and capecitabine was commenced, and resulted in partial remission of the colorectal carcinoma. Simultaneously, the indurations of the forearms and calves also improved, suggesting that the eosinophilic fasciitis was a paraneoplastic phenomenon.

Colorectal cancer treatment and survival: the experience of major public hospitals in south Australia over three decades.

BACKGROUND Registry data from four major public hospitals indicate trends in clinical care and survival from colorectal cancer over three decades, from 1980 to 2010. MATERIALS AND METHODS Kaplan-Meier product- limit estimates and Cox proportional hazards models were used to investigate disease-specific survival and multiple logistic regression analyses to explore first-round treatment trends. RESULTS Five-year survivals increased from 48% for 1980-1986 to 63% for 2005-2010 diagnoses. Survival increases applied to each ACPS stage (Australian Clinico-Pathological Stage), and particularly stage C (an increase from 38% to 68%). Risk of death from colorectal cancer halved (hazards ratio: 0.50 (0.45, 0.56)) over the study period after adjusting for age, sex, stage, differentiation, primary sub-site, health administrative region, and measures of socioeconomic status and geographic remoteness. Decreases in stage were not observed. Survivals did not vary by sex or place of residence, suggesting reasonable equity in service access and outcomes. Of staged cases, 91% were treated surgically with lower surgical rates for older ages and more advanced stage. Proportions of surgical cases having adjuvant therapy during primary courses of treatment increased for all stages and were highest for stage C (an increase from 5% in 1980-1986 to 63% for 2005-2010). Radiotherapy was more common for rectal than colonic cases. Proportions of rectal cases receiving radiotherapy increased, particularly for stage C where the increase was from 8% in 1980-1986 to 60% in 2005-2010. The percentage of stage C colorectal cases less than 70 years of age having systemic therapy as part of their first treatment round increased from 3% in 1980-1986 to 81% by 1995-2010. Based on survey data on uptake of adjuvant therapy among those offered this care, it is likely that all these younger patients were offered systemic treatment. CONCLUSIONS We conclude that pronounced increases in survivals from colorectal cancer have occurred at major public hospitals in South Australia due to increases in stage-specific survivals. Use of adjuvant therapies has increased and the patterns of change accord with clinical guideline recommendations. Reasons for sub-optimal use of radiotherapy for rectal cases warrant further investigation, including the potential for limited rural access to impede uptake of treatments at metropolitan-based radiotherapy centres.

Phase I study evaluating the safety and efficacy of oral panobinostat in combination with radiotherapy or chemoradiotherapy in patients with inoperable stage III non-small-cell lung cancer.

Panobinostat is a radiosensitizing agent and targets the epigenetics of malignancy. This phase I study evaluated the safety and efficacy of combining oral panobinostat with radiotherapy (RT) or chemoradiotherapy (CRT) in patients with inoperable stage III non-small-cell lung cancer. This study had a parallel dose-escalating design combining oral panobinostat twice a week (dose escalations 20, 30, 45 mg) with either palliative RT (group A) or radical CRT (group B) using a standard chemotherapy protocol of cisplatin and etoposide. In group A (RT), nine recruited patients received treatment with oral panobinostat (doses 20, 30, 45 mg) with RT. Two serious adverse events, rapid atrial fibrillation and tracheo-oesophageal fistula, were not attributable to study treatment. The most common grade 3/4 toxicities were thrombocytopenia and lymphopenia, which resolved promptly after cessation of panobinostat. The disease control rate was 66%, the progression-free survival was 3 months and the median overall survival was 9 months. In group B (CRT), panobinostat dose was not escalated beyond 20 mg because of infection-related complications. Serious adverse events included opportunistic infection associated with treatment-related lymphopenia and febrile neutropenia without a source. One patient had cerebral infarct that was not attributed to study treatment. All patients achieved a partial response to treatment. At 33 months of follow-up, all patients were still alive. Panobinostat can be combined with palliative-dose RT at doses up to 45 mg twice a week with tolerable toxicity. Dose-limiting toxicities prevented the dose escalation of the panobinostat with CRT.

PRISM: Phase 2 trial with panitumumab monotherapy as second‐line treatment in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

Panitumumab Regimen In Second‐line Monotherapy of Head and Neck Cancer (PRISM) trial evaluated the safety and efficacy of panitumumab as second‐line monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Statin use and pain in older people with cancer: a cross-sectional study.

To investigate statin use and pain in people with cancer aged 70 to 79 and 80 and older.

A phase Ib/II study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in metastatic colorectal cancer with KRAS wild type (WT).

TPS162 Background: Activation of the EGFR results in cell proliferation and survival via the RAS/RAF/MAPK, and PI3K/PTEN/AKT signalling pathways. Mutations in the KRAS gene result in a constitutively active protein that is independent of the EGFR and therefore is not inhibited by anti-EGFR monoclonal antibodies. However, recent retrospective studies have shown that aberrations in other down stream signalling molecules also confer resistance to EGFR antagonists, including mutations in BRAF and PI3K, and loss of the PTEN tumour suppressor molecule. The mammalian target of rapamycin (mTOR) is a key downstream regulatory protein that is activated via the PI3K-AKT pathway, and regulates cell growth, proliferation, and survival. Inhibition of mTOR in addition to blockade of the EGFR may cause a more profound anti-tumour effect by overcoming upstream mechanisms of resistance. In EGFR-resistant colon cancer cell lines, in vitro and in vivo studies of the combination of everolimus and an EGFR inhibitor resulted in reduced tumour growth and resensitised resistant cancer cells to EGFR inhibition (Bianco. B J Cancer 2008:923-930). METHODS This is a phase Ib/II, open label, non-randomised study. Eligibility criteria include age ≥ 18 years, metastatic colorectal cancer that is KRAS wild type, following failure of first-line oxaliplatin and fluoropyrimidine combination chemotherapy, with adequate bone marrow reserve and organ function. Patients receive IV irinotecan and panitumumab every 2 weeks, with everolimus administered orally thoughout the 14 day cycle. The starting dose is irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate days. Dose finding will use a standard 3+3 design with the MTD being defined as the dose with DLTs in 1/6 or fewer patients. Following determination of the MTD, the phase II component of the study will begin for which the primary endpoint is response rate. A total of 50 patients will be recruited. Correlation of response rate with BRAF mutation, expression of PTEN, ERK, AKT, mTOR, and pS6K will be performed.

GM-CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid-derived suppressor cells in vitro

Immune evasion is a recently defined hallmark of cancer, and immunotherapeutic approaches that stimulate an immune response to tumours are gaining recognition. However tumours may evade the immune response and resist immune‐targeted treatment by promoting an immune‐suppressive environment and stimulating the differentiation or recruitment of immunosuppressive cells. Myeloid‐derived suppressor cells (MDSC) have been identified in a range of cancers and are often associated with tumour progression and poor patient outcomes. Pancreatic cancer in particular supports MDSC differentiation via the secretion of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and MDSC are believed to contribute to the profoundly immune‐suppressive microenvironment present in pancreatic tumours. MDSC‐targeted therapies that deplete or inhibit this cell population have been proposed as a way to shift the balance in favour of a tumour‐clearing immune response. In this study, we have modelled MDSC differentiation and function in vitro and this has provided us with the opportunity to test a range of potential MDSC‐targeted therapies to identify candidates for further investigation. Using in vitro modelling we show here that the combination of GM‐CSF‐signalling blockade and gemcitabine suppresses both the MDSC phenotype and the inhibition of T‐cell function by MDSC.