Neuropeptide growth factors and small cell lung cancer

Quiescent cultures of Swiss 3T3 cells are a useful model system for elucidating the mechanisms of mitogenesis. Here, Swiss 3T3 cells were used to test novel mitogens and characterise bombesin antagonists. Bradykinin was identified as a potent mitogen, acting in synergy with insulin. Two groups of antagonists were characterised: the substance P analogues [DArg1, DPro2, DTrp7,9, Leu11]- substance P (antagonist A), [DArg1, DPhe5, DTrp7,9, Leu11]- substance P (antagonist D) and [Arg6, DTrp7,9, Leu11] substance P(6-11) (antagonist G); and the bombesin-specific antagonists (Leu13-psi(CH2NH)Leu14]bombesin and N- acetyl-GRP(20-26). The substance P antagonists appear to interact with a common domain on the receptors for three mitogenic neuropeptides in Swiss 3T3 cells: bombesin, vasopressin and bradykinin. The bombesin-specific antagonists did not interact with other receptors. Small cell lung cancer (SCLC) is an aggressive form of lung cancer. The bombesin-like peptides, including gastrin- releasing peptide (GRP), have been postulated to act as autocrine growth factors for these tumours. In SCLC cell lines, all the antagonists were shown to block the early effect of bombesin, mobilisation of cytosolic Ca2+. The substance P antagonists also inhibited SCLC growth in liquid and semisolid media, in a reversible, dose-dependent fashion. The bombesin-specific antagonists did not inhibit SCLC growth, suggesting that other growth factors blocked by the substance P antagonists may be more important for regulating SCLC growth. A variety of peptides and hormones were tested for their ability to mobilise cytosolic Ca2+ in SCLG cell lines. Ca2+ signals were induced by GRP, vasopressin, bradykinin, cholecystokinin, galanin and neurotensin, and all were blocked by antagonists D and G. These neuropeptides are suggested as possible growth factors for SCLC

Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate

Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments

Relative Hypocalcaemia and Muscle Cramps in Patients Receiving Imatinib for Gastrointestinal Stromal Tumour

Purpose. Imatinib treatment causes muscle cramps in up to 40% of patients, but their pathogenesis is unknown. We present a case series illustrating an association between imatinib, relative hypocalcaemia, and the development of cramps. Patients. The index patient developed muscle spasms and cramps after receiving imatinib for gastrointestinal stromal tumour (GIST) for 5 months. The adjusted serum calcium had dropped to the lower limit of normal. The low serum calcium and muscle cramps improved on stopping imatinib and recurred on rechallenge. We reviewed the medical records of 16 further patients. Results. Two patients reported muscle cramps (12%). There was a rapid and sustained reduction in adjusted serum calcium in the first 6 months from 2.45 ± 0.11 mmol/L (mean ± SD) to 2.30 ± 0.08 mmol/L (p = 0.025). Conclusion. Imatinib treatment of GIST is associated with reduction in serum calcium which may explain the development of neuromuscular symptoms. In patients receiving imatinib, serum electrolytes should be monitored and muscle cramps treated by correction of serum calcium, or an empirical trial of quinine sulphate

A Phase II Nonrandomised Open-Label Study of Liposomal Daunorubicin (DaunoXome) in Advanced Soft Tissue Sarcoma

Thirty four patients with advanced soft tissue sarcoma not previously treated with an anthracycline were treated with DaunoXome 100mg/m2 every 3 weeks. Thirty-three patients were evaluable for toxicity. Grade 3-4 neutropenia was seen in 20 patients (60.6%), complicated by febrile neutropenia in 2 (6.1%). Other grade 3 toxicities were rare. Among 32 patients assessable for response, one patient had a partial response, giving a response rate of 3.13% (95% confidence interval, 0.08–16.22%). Seven patients (21.9%) had stable disease, and 24 patients (75.0%) had disease progression. The median time to progression for all patients was 42 days (95% CI, 39–49) and the progression-free rate at 3 months was 12.5%. In conclusion, DaunoXome at this dose and schedule is well tolerated in patients with advanced soft tissue sarcoma, but is not associated with significant activity. Further studies at this dose and schedule cannot be recommended in this disease

Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata

Background: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer. // Methods: Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon’s two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata. // Results: Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events. // Conclusions: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials. // Clinical Trial Registration: ISRCTN 6079133

Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update

Summary: Angiosarcomas are rare aggressive endothelial tumours, and are associated with a poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. A number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field

Ganetespib in combination with pemetrexed-platinum chemotherapy in patients with pleural Mesothelioma (MESO-02) : a phase Ib trial

Purpose: Ganetespib, a highly potent, small molecule Heatshock protein 90 inhibitor, has potential efficacy in malignant pleural mesothelioma (MPM) via activity on critical survival pathways and known synergies with antifolates and platinum chemotherapy. We conducted a dose-escalation study to identify the Maximum Tolerated Dose (MTD) of ganetespib in chemotherapy-naïve MPM patients. Experimental Design: MESO-02 (ClinicalTrials.gov: NCT01590160) was a non-randomized, multicentre, phase Ib trial of 3-weekly ganetespib (100 mg/m2, 150 mg/m2, 200 mg/m2; days 1 and 15) with pemetrexed (500 mg/m2; day 1) and cisplatin (75 mg/m2; day 1) or carboplatin (area under concentration-time curve 5; day 1) in MPM patients. Dose-escalation was performed using the 3+3 design (cisplatin) and accelerated titration design (carboplatin). Secondary endpoints included best response, progression-free survival (PFS) and pharmacogenomic analyses. Results: Of 27 patients enroled (cisplatin, n=16; carboplatin, n=11), 3 experienced dose-limiting toxicities: grade 3 nausea (cisplatin, n=1; carboplatin, n=1); grade 2 infusion-related reaction (carboplatin, n=1). Ganetespib's MTD was 200 mg/m2. Partial response was observed in 14/27 patients (52%; 61% in 23 response-evaluable patients) and 13/21 (62%) with epithelioid histology. At the MTD, 10/18 patients (56%) had partial response, 15/18 (83%) had disease control, and median PFS was 6.3 months (95% CI 5.0-10.0). One responder exhibited disease control beyond 50 months. Global Loss of Heterozygosity was associated with shorter time to progression (Hazard Ratio 1.12, 95% CI 1.02-1.24; p=0.018). Conclusions: Ganetespib can be combined safely with pemetrexed and platinum chemotherapy to treat patients with MPM. This class of agent should be investigated in larger randomized studies

Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.

BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m(2) on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m(2) on days 1 and 8 and intravenous docetaxel 75 mg/m(2) on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7-29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5-54·6] vs 46·4% [37·5-54·8]); median progression-free survival (23·3 weeks [95% CI 19·6-30·4] vs 23·7 weeks [18·1-20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99-1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.

BACKGROUND: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. METHODS: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. FINDINGS: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95-1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI -3·2% to 13·7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). INTERPRETATION: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. FUNDING: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups)