T. de Baere

Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours

A few studies have suggested an antitumour activity of somatostatin analogues in neuroendocrine tumours (NET). The aim of this study was to evaluate the antitumour efficacy of somatostatin analogues in patients with documented progressive tumours. 35 consecutive patients with documented tumour progression were treated with somatostatin analogues. Patients were classified into two groups. In Group 1, tumours were progressing rapidly (an increase of 50% or more in the lesion surface area in 3 months) and in Group 2, tumours were progressing more slowly (an increase of less than 50% in the lesion surface area in 3 months but greater than 25% in 6 months). Treatment consisted of subcutaneous (s.c.) octreotide, 100 microg thrice daily for 17 patients, intramuscular lanreotide, 30 mg/every 14 days for 11 patients and for 7 patients both somatostatin analogues were used successively during the follow-up. Primary tumour sites were the small intestine (n=12), pancreas (n=13), lungs (n=5), and other sites (n=5). 18 patients had the carcinoid syndrome with flushing and/or diarrhoea. The median duration of treatment was 7 months. Treatment was discontinued in 3 patients due to side-effects. One patient (3%) achieved a partial response and the disease was stabilised in 20 patients (57%) for a median duration of 11 months (6-48 months). Stabilisation of patients in Group 1 was significantly less frequent at 6 months than that of patients in Group 2 (4/12 and 13/17 respectively, P<0.02). Somatostatin analogue treatment resulted in one partial response (3%) and 20 cases of stabilisation (57%) in 35 patients with progressive NET. A slow tumour growth rate before treatment is predictive of a good response to somatostatin analogues which could be considered an option for first-line treatment.

Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566 patients with 1037 metastases

Radiofrequency of lung metastases below 4 cm, demonstrated an overall survival of 62 months, associated with a 4-year local efficacy of 89%. Repeatability of the technique allows a 4-year lung disease control rate of 44.1%, with patient retreated safely up to four times. Radiofrequency is an option for treatment of small size lung metastases, namely the ones below 2 to 3 cm in diameter.

Incidence of Unsuspected and Treatable Metastatic Disease Associated With Operable Colorectal Liver Metastases Discovered Only at Laparotomy (and Not Treated When Performing Percutaneous Radiofrequency Ablation)

BackgroundWhen patients with resectable colorectal liver metastases (LM) are treated with percutaneous radiofrequency (RF), some unsuspected intrahepatic and extrahepatic metastases, detectable only at laparotomy, might be ignored and left untreated. This would result in a reduced cure rate. Our purpose was to discover the incidence of unsuspected and surgically treatable intrahepatic and extrahepatic metastases discovered at laparotomy.MethodsThe data of 506 patients who underwent a laparotomy and then a hepatectomy for colorectal LM were prospectively collected and retrospectively analyzed. All patients had undergone at least two types of preoperative liver imaging (but no fluorodeoxyglucose-positron emission tomography).ResultsUnsuspected metastases were discovered at laparotomy in 209 patients (41.3%). There were extrahepatic metastases in 82 patients (16.2%), additional LM in 152 patients (30%), and both in 25 patients (4.9%). Liver palpation and intraoperative ultrasound allowed for detecting additional LM in 125 (24.7%) and 48 (9.4%) patients, respectively. All of them were resected. When only the 124 patients who presented with 1 to 3 LM measuring <3 cm in diameter (candidates for percutaneous RF) were considered, the results were similar. Moreover, the incidence of unsuspected metastases was similar when the periods of surgery (before and after January 1996) were considered.ConclusionsLaparotomy permits discovery of and treatment with a curative intent of unsuspected intrahepatic or extrahepatic metastases in at least one third of patients with classically resectable colorectal LM. This does not support the use of percutaneous RF ablation instead of hepatic resection for this population, because it will result in an important survival decrease.

Prediction and diagnosis of bone metastases in well-differentiated gastro-entero-pancreatic endocrine cancer: a prospective comparison of whole body magnetic resonance imaging and somatostatin receptor scintigraphy.

PURPOSE Our purpose was to compare the sensitivity of whole body (WB) magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS) for the diagnosis of bone metastases (BMs) in patients with well-differentiated gastro-entero-pancreatic endocrine cancer (WD-GEP-EC) and to determine predictive factors of BM. PATIENTS AND METHODS WB-MRI and SRS were prospectively performed in 79 patients with bronchial (11), thymic (five), gastric (two), duodeno-pancreatic (24), ileal (26), colic (one), or unknown primary (10) WD-GEP-EC. RESULTS A total of 36 patients (46%) had 333 BMs involving 119 skeletal segments. WB-MRI and SRS were equally sensitive for detecting patients with BM (86 vs. 81%; P = 0.56), with 33% of the patients diagnosed with only one procedure. WB-MRI detected more BMs than SRS (80 vs. 57%; P = 0.017). Compared with SRS, WB-MRI detected more spine BMs (96 vs. 45%; P < 0.001) and tended to detect more pelvic and lower limb BMs (P = 0.054 and P = 0.06, respectively). Compared with WB-MRI, SRS detected more skull BMs (100 vs. 0%; P < 0.001) and tended to detect more rib BMs (P = 0.08). Sternal and upper-limb BMs were equally detected with WB-MRI and SRS (P = 0.32 and P = 0.46, respectively). Bone staging with SRS and spine MRI rather than WB-MRI would have detected 92% of the patients with BMs and 83% of all BMs. The extent of liver involvement and bronchial-thymic primary tumors were independent predictive factors for BM. CONCLUSIONS We recommend bone staging with SRS and spine MRI in all patients with bronchial-thymic or unknown primary WD-GEP-EC. In case of duodeno-pancreatic or ileal primary, bone imaging may be restricted to patients with liver metastases.

Sequential research-related biopsies in phase I trials: acceptance, feasibility and safety

BACKGROUND Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies. PATIENTS AND METHODS From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies. RESULTS Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridization array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies. CONCLUSIONS In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.BACKGROUND Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies. PATIENTS AND METHODS From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies. RESULTS Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridizartion array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies. CONCLUSIONS In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.

Endocrine pancreatic tumours: which are the most useful MRI sequences?

ObjectivesTo determine magnetic resonance imaging (MRI) signal and enhancement characteristics of endocrine pancreatic tumours (ETPs) and which MR sequences show them most consistently.MethodsFifty-five consecutive patients with 68 ETPs underwent 1.5-T abdominal MRI comprising T2-weighted, unenhanced T1-weighted and dynamic T1-weighted after injection of gadopentetate dimeglumine sequences. Twenty-one patients underwent diffusion-weighted imaging (DWI). Two radiologists identified the number, location, size, signal and enhancement patterns of ETPs, and determined a confidence scale indicating the presence of tumours on DWI. The results were compared with echo-endoscopy (endoscopic ultrasound) findings.ResultsThe detection sensitivity was 95%, similar to that of echo-endoscopy. T2-weighted and T1-weighted sequences at the arterial phase had the highest contrast-to-noise ratio (CNR) median value. On DWI, the mean sensitivity was 65%. The mean apparent diffusion coefficient (ADC) value of ETP was significantly lower than in the normal parenchyma.ConclusionIn suspected ETP, MRI is a sensitive method, similar to echo-endoscopy and could be recommended as the first imaging technique. T2-weighted sequences and T1-weighted sequences in the arterial phase are the optimal pulse sequences. The quantitative assessment of ADC values is a promising tool for the characterisation of pancreatic lesions.

Percutaneous ablation of bone tumors

Percutaneous ablation (radiofrequency or cryotherapy) of bone tumors is most often performed for palliative purposes. Many studies have shown that percutaneous ablation of a painful bone metastasis can significantly and sustainably reduce symptoms. It is therefore an alternative to radiotherapy and to long-term opiates. Percutaneous ablation can also be performed for curative purposes. In this situation, its efficacy has however only been studied to a very small extent (apart from radiofrequency ablation of osteoid osteomas in which the success rate is almost 100%). In our experience, the success rate after radiofrequency ablation of a bone metastasis is 75% if it is less than 3cm in diameter and fall significantly over this (to 40%, P=0.04). This treatment can therefore be justified in oligometastatic patients whose disease is progressing slowly. Its benefit on survival has however not been assessed in this selected population. Whether it is performed for palliative or curative reasons, percutaneous ablation should ideally be followed by an injection of cement if the metastasis being treated is lytic and located in a bone, which is subject to mechanical forces. The aim of consolidating cementoplasty is to counterbalance the additional risk of fracture due to destruction of the percutaneously ablated bone.

Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV

BACKGROUND Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS EUDRACT 2007-004632-24, NCT00852228.

New tumor ablation techniques for cancer treatment (microwave, electroporation)

Since the introduction of radiofrequency ablation (RFA) for the treatment of liver tumors at the end of the 1990s, indications for local ablation techniques have been extended to other organs, in particular, the lungs, kidneys and bones. These techniques have also been improved, in particular to try and overcome the limitations of radiofrequency techniques, especially the significant decrease in complete ablation rates for tumors larger than 3cm and tumors that are contiguous to vessels larger than 3mm. Microwave ablation is a rapidly developing thermal ablation technique similar to RFA but with numerous differences. Electroporation, a non-thermal ablation technique with other possibilities, is in earlier stages of clinical development.

Cementoplasty of bone metastases

Cementoplasty is a palliative treatment for bone metastases. It can be performed alone or in addition to other treatments, such as radiotherapy, radiofrequency ablation or cryotherapy. It is usually performed to reduce pain where the metastases involve the spine and pelvis. It can also be used to stabilise bones in the event of lytic metastases with a risk of fracture. Unlike ablation techniques, it should not be considered a cancer treatment.