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A randomised phase II study comparing capecitabine plus streptozocin with or without cisplatin chemotherapy as treatment for unresectable or metastatic neuroendocrine tumours
Neuroendocrine tumours (NETs) are very rare cancers, incidence around 1-2/100,000/year, with characteristically indolent behaviour. The mainstay of treatment is surgical resection. However, many tumours metastasise and cannot be removed, while their behaviour changes to become more aggressive over time such that median life expectancy for patients with liver metastases is approximately 2 years. A range of therapeutic modalities are available for treatment of metastatic disease. The choice of treatment offered to individual patients depends on whether the disease is hormonally functional and includes manipulation with somatostatin analogues, radioisotope therapy and hepatic arterial embolization. Despite their low growth rate, pancreatic and certain foregut (gastric and bronchial) NETs are considered to be chemosensitive and responses have been reported with a range of cytotoxic agents, in particular, streptozocin, 5-fluorouracil (5FU), doxorubicin, cisplatin and etoposide. A significant proportion of NET patients present with metastatic disease, yet, despite optimal investigations, a primary site cannot be identified. This group of tumours may be a mixture of midgut, duodenal and pancreatic NETs, some of which may respond to chemotherapy.
This trial proposed to randomise patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumours to receive one of 2 combination chemotherapy regimens: capecitabine plus streptozocin (‘cap-strep’), or capecitabine plus streptozocin plus cisplatin (‘cap-cist’). This is a randomised phase II study to determine the feasibility, toxicity and efficacy of 2 combination chemotherapy regimens, capecitabine plus streptozocin (‘cap-strep’) and capecitabine plus streptozocin plus cisplatin (‘cap-cist’) in the treatment of unresectable or metastatic gastroenteropancreatic neuroendocrine tumours. The primary objective of the study is objective response rate. The secondary objectives are overall (objective and biochemical) response rate, functional response, toxicity, progression-free and overall survival and quality of life. Paraffin-embedded tumour tissue and a single blood sample will be collected from patients for pathological and molecular marker studies. The results of this randomised phase II study will be used as a basis from which to design a first UK phase III trial of systemic therapy for NETs, supported by the UK NETwork multidisciplinary group and the NCRI Upper GI clinical studies group.
Main inclusion criteria
Patients with histological confirmation of unresectable, advanced and/or metastatic:
- Gastroentero-neuroendocrine tumour of the foregut,
- Pancreatic neuroendocrine tumour,
- Neuroendocrine tumour of unknown primary
Measurable disease, defined by the presence of at least 1 lesion which can be accurately measured in at least 1 dimension with longest diameter > 20 mm using conventional CT scanning, or > 10 mm with spiral CT or MRI.
No prior or concomitant chemotherapy administered for this condition
Life expectancy > 12 weeks,
Performance status 0, 1 or 2 (ECOG performance scale.
Age > 18 years
- Hb > 10 g/dl, platelets > 100 x109/L, WCC > 3.0 x109/L, ANC > 1.5x109/L
- Bili < 2 x ULN, Alk phos < 5 x ULN, transaminases < 5 x ULN
Cockroft/Gault calculated GFR > 60 ml/min
Written informed consent provided by the patient
Women of child-bearing potential must have a negative pregnancy test prior to study entry and be using adequate contraception, which must be continued for 3 months after the study
Main exclusion criteria
Although bronchial NETs constitute a significant number of foregut NETs which are also considered to be chemosensitive, these tumours are conventionally offered platinum-based chemotherapy and hence this study excludes bronchial NETs. Other NETs where the primary site is situated in organs above the diaphragm (eg. laryngeal and pharyngeal NETs) are also excluded.
No previous systemic chemotherapy or chemotherapy administered as part of a chemo-embolisation regimen is allowed. Prior interferon therapy is allowed. In this case, the time interval between the last dose of interferon and the date of commencing chemotherapy within this trial should be at least 3 weeks.
Any previous receptor-targeted radiolabelled therapy in the last 6 months
Any previous investigational agent within the last 4 weeks
Patients may have previously received somatostatin analogues. Patients on somatostatin analogues are eligible to enter the study if their symptoms are no longer controlled by this treatment or there is documented measurable disease progression on serial CT scans performed up to 6 months apart, as defined by RECIST criteria. At the time of trial entry, it is acceptable for the patient to continue their somatostatin analogue therapy or to stop it, depending on individual circumstances.
Palliative radiotherapy involving any of the lesion(s) being used to measure disease. Palliative radiotherapy to regions not involved in measurement of disease is permitted.
Any other serious or uncontrolled illness which, in the opinion of the investigator, makes it undesirable for the patient to enter the trial
Any medical or psychiatric condition which would influence the ability to provide informed consent
Pregnant or lactating women
Funders and sponsors
Dr Pippa Corrie
Cancer Theme Email: firstname.lastname@example.org