Sarah Slater

The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rapidly progressive invariably lethal tumor. Treatment options remain limited and the outcome in relapsed disease is poor warranting new therapeutic options. Following our previous experience in the first-line setting, we conducted a phase 2 open-label non-comparative study to assess the safety and efficacy of weekly vinorelbine chemotherapy, each cycle consisting of 30 mg/m(2) for 6 weeks, in patients with previous exposure to chemotherapy. In 63 individuals with relapsed MPM who had not received previous vinorelbine, we observed an objective response rate of 16% and an overall survival of 9.6 months (95% confidence interval 7.3-11.8 months). The main grade III/IV toxicity observed was neutropenia and toxicity was similar to weekly vinorelbine when used in the first-line setting. Weekly vinorelbine appeared to have a reasonable response rate with an acceptable toxicity profile in the second-line treatment of MPM. Its use should be prospectively evaluated in a randomised trial in the first or second-line therapy of MPM.

A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3)

LBA4000 Background: EGFR overexpression occurs in 27-50% of esophagogastric adenocarcinomas (OGA), and correlates with poor prognosis. The REAL3 trial evaluated the addition of the anti-EGFR antibody panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in advanced OGA. METHODS Patients with untreated, metastatic or locally advanced OGA were randomised to EOC (E 50mg/m2, O 130mg/m2, C 1250mg/m2/day) or mEOC+P (E 50mg/m2, O 100mg/m2, C 1000mg/m2/day, P 9mg/kg). Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST after 4 and 8 cycles. Following IDMC review in October 2011 trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. RESULTS 553 patients were recruited (EOC 275, mEOC+P 278), with median follow-up 5.0 and 5.2 months respectively. Median OS was 11.3 months with EOC compared to 8.8 months with mEOC+P (HR 1.37: 95% CI 1.07-1.76, p=0.013). Median PFS was 7.4 and 6.0 months respectively (HR 1.22: 95% CI 0.98-1.52, p=0.068), with RR being 42% compared to 46% (odds ratio 1.16: 95% CI 0.81-1.57, p=0.467). mEOC+P was associated with ↑ G3/4 diarrhoea (17% vs 11%), skin rash (14% vs 1%) and thrombotic events (12% vs 7%), but ↓ haem toxicity (>G3 neutropenia 14% vs 31%). In the mEOC+P arm, OS was significantly improved in patients with G1-3 rash (77%, n=209) on treatment compared to those without (23%, n=63); median OS 10.2 vs 4.3 months (p<0.001), with similar significant improvements seen in RR and PFS. Biomarker analysis in the first 200 patients has not identified other predictive markers associated with P therapy. Multivariate analysis for OS in these patients demonstrated a negatively prognostic role for KRAS mutation (HR 2.1: 95% CI 1.10-4.05, p=0.025) and PIK3CA mutation (HR 3.2: 95% CI 1.01-10.40, p=0.048). CONCLUSIONS Addition of P to EOC chemotherapy was associated with worsening of OS in an unselected advanced OGA population. This may be in part due to lowered doses of O and C in the mEOC+P regimen. Outcomes in patients treated with P varied by grade of skin toxicity.

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report

BACKGROUND Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Long‐term outcome of patients surviving for more than ten years following treatment for acute leukaemia

Between 1972 and 1988, 832 consecutive patients were treated for acute leukaemia at St. Bartholomews Hospital; a retrospective analysis has been conducted to determine the clinical course and outcome for 101 who have survived ≥ 10 years following treatment. At a median follow‐up of 16 years (range 10–28 years), 86 patients (86 out of 834 total, 11%) were still alive. Long‐term follow‐up of patients who have survived ≥ 10 years following treatment for acute leukaemia revealed that most patients were in normal health, although a significant number of complications had occurred.

A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: Results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO)

BACKGROUND The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan. METHODS Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation. RESULTS The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference. INTERPRETATION The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC. FUNDING The trial was funded by Cancer Research UK and supported by Amgen Pharma.

Primary Esophageal Carcinoma in the Era of Highly Active Antiretroviral Therapy

BACKGROUND As human immunodeficiency virus (HIV)-infected individuals are living longer, non-AIDS-defining cancers are becoming increasingly recognized. Primary esophageal tumors in people living with HIV have seldom been reported. We sought to document patient, virologic, and tumor characteristics and clinical outcomes in this patient group. METHODS International physicians involved in the care of AIDS-defining and non-AIDS-defining cancers accrued cases of primary esophageal malignant neoplasms in HIV-infected individuals. Patient demographics, HIV status, cancer risk factors, esophageal tumor characteristics, treatment, and outcomes were analyzed. RESULTS A total of 19 patients with primary adenocarcinoma and/or squamous cell carcinoma of the esophagus were identified. The median age was 48 years (range, 35-69 years) and the median CD4 lymphocyte count measured 376 cells/microL (range, 42 to >1000 cells/microL) (to convert to x10(9)/L, multiply by 0.001). The majority of patients were men with a history of smoking or considerable alcohol consumption. Prior esophageal disease (reflux, peptic ulcers, and achalasia) was reported in almost half of all patients. Seven patients (37%) underwent surgical resection, 11 (58%) received fluorouracil-based chemotherapy, and 7 (37%) underwent radiotherapy; survival correlated with stage at cancer presentation. While the majority of patients died, only 5 deaths (26%) were attributed to progression of esophageal carcinoma. CONCLUSIONS Primary esophageal carcinoma is another non-AIDS-defining cancer associated with moderate immunosuppression and lifestyle habits including tobacco and alcohol use. The biological behavior, treatment, and outcome of HIV-related esophageal cancer appear similar to the general population with this disease; the same screening and risk moderation strategies are likely to apply.

Molecular characterization of a new recombination of the SIL/TAL-1 locus in a child with T-cell acute lymphoblastic leukaemia

Summary. Deletions involving the SIL‐TAL‐1 locus are seen in 15% of T‐acute lymphoblastic leukaemias (T‐ALL). To date, seven deletions have been described, spreading over 90 kb of chromosome 1, fusing SIL to the TAL‐1 gene and resulting in over expression of TAL‐1. During the diagnostic screening of the TAL‐1 deletion in 176 T‐ALL patients, we identified one case showing a new SIL rearrangement. A novel fusion transcript was identified between the SIL exon 1a and an unknown sequence (633‐cDNA). Polymerase chain reaction (PCR) screening of a human cDNA library confirmed the existence of this transcript. Using long‐distance PCR on patient DNA, we obtained a genomic fragment containing SIL exon 1b, a portion of intron 1b, an unknown sequence and the 633 sequence. Using DNA from healthy donors, a partial genomic map of 633‐DNA was found to be identical to the restriction map of the PCR fragment amplified from patient DNA. To define the chromosomal origin of 633‐DNA, a YAC human genomic library was screened. Two clones containing 633‐DNA were found, mapping to chromosomal region 1p32 and both contained SIL and TAL‐1 sequences. By searching GenBank, we identified PAC RP1‐18D14 which contains SIL, TAL‐1 and 633‐DNA, confirming this novel rearrangement as a new deletion of the SIL/TAL‐1 locus.

Phase II trial of irinotecan, cisplatin and mitomycin for relapsed small cell lung cancer.

There is no standard therapy for relapsed small cell lung cancer (rSCLC). We evaluated the efficacy and toxicity of a new triplet consisting of irinotecan (100 mg/m2 Days 1 and 15 q28), cisplatin (40 mg/m2 Days 1 and 15 q28) and mitomycin (6 mg/m2 d1 q28) administered to a maximum of 6 cycles in individuals with rSCLC that had relapsed following first line treatment. Partial remisions were observed in 35% and progression in 30% of patients. Progression free survival measured 4.5 months (95% CI 0.8–8.2) and overall survival was 7.8 months (95% CI 5.3–10.3). QoL showed improvement in activity symptoms and stabilization of physical symptoms. As IPM was a well‐tolerated regimen with activity in rSCLC, a phase III trial comparing this triplet with other regimens in this setting is warranted.

Monoclonal Epstein-Barr virus-related lymphoproliferative disorder following adult acute lymphoblastic leukaemia.

A 31‐year‐old patient in remission of acute lymphoblastic leukaemia (ALL), receiving oral maintenance chemotherapy (6‐mercaptopurine, methotrexate (MTX), cyclophosphamide), developed a monoclonal, Epstein‐Barr virus (EBV)‐related lymphoproliferative disorder (LPD). Treatment consisted of excisional biopsy and the discontinuation of maintenance chemotherapy. To our knowledge, this is the first such report in an adult. The histological similarity to previous reports of ‘lymphomatoid granulomatosis’ following paediatric ALL suggests that they are the same disease. MTX may play a central role in the development of LPD in this setting. Although it is a rare complication of ALL, EBV‐related LPD should be considered in patients who develop lymphadenopathy.

Long-term collaboration for building sustainable palliative care in Belarus.

142 Background: The WHO and the Worldwide Palliative Care Alliance have published findings that only 10% of the 20.4 million people who need palliative care currently receive it. A major barrier to meeting that need is insufficient education of healthcare workers in palliative care. Over the last decade, palliative care has attracted significant interest from the government of Belarus, with the first adult hospice founded in 2005 and introduced palliative care into the National Healthcare Law in 2013. However, the country faces a shortage of healthcare providers trained in palliative care. We report on the experience of developing and implementing a palliative care curriculum in Belarus. METHODS We first conducted a needs assessment that examined physician knowledge of and attitudes toward palliative care, the legal status of palliative care, drug availability, and other topics. We utilized past in-country experience, a literature review, a questionnaire, and interviews with Belarusian colleagues. Based on the needs assessment, we developed, modified, and translated a 25-lecture curriculum that was comprehensive, at an adequate difficulty level, and culturally appropriate. A team of four clinicians taught the curriculum in Belarus over to an audience of physicians, and healthcare administrators. RESULTS The course was well-received-participants were satisfied, reported a better understanding of palliative care, and improved their skills and confidence in managing symptoms and discussing prognosis. CONCLUSIONS We have continued our collaboration with our Belarusian colleagues. New government policies and have passed which promote palliative care. We subsequently held a web-based teleconference with members of the Ministry of Health as well has medical education administrators in Belarus to discuss the structure of palliative care programs in the United States and our model of palliative care education. A second in-person palliative care education workshop for both physicians and nurses is being planned for the fall of 2015. We hope that our experience provides encouragement and resources for the continued promotion of palliative care education and development worldwide.