Johannes H.W. de Wilt

Current uses of isolated limb perfusion in the clinic and a model system for new strategies

Isolated limb perfusion with melphalan is the treatment of choice for multiple (small) melanoma-in-transit metastases. The use of tumour necrosis factor alpha (TNFalpha) in isolated limb perfusion is successful for treatment of locally advanced limb soft-tissue sarcomas and other large tumours; this approach can avoid the need for amputation. TNFalpha was approved in Europe after a multicentre trial in patients with locally advanced soft-tissue sarcomas, deemed unresectable by an independent review committee; the response rate to isolated limb perfusion with TNFalpha plus melphalan was 76% and the limb was saved in 71% of patients. Moreover, the trial showed the efficacy of isolated limb perfusion of TNFalpha and melphalan against various other limb-threatening tumours such as skin cancers and drug-resistant bony sarcomas. Laboratory models of isolated limb perfusion have helped to elucidate mechanisms of action and to develop new treatment modalities. They have identified TNFalpha-mediated vasculotoxic effects on the tumour vasculature and have shown that addition of TNFalpha to the perfusate results in an increase of three to six times in uptake of melphalan or doxorubicin by tumours. New vasoactive drugs and new mechanisms of action are being discovered. Moreover, isolated limb perfusion is an effective modality for gene therapy mediated by an adenoviral vector. Various clinical phase I-II studies can be expected in the next few years.

Isolated hypoxic hepatic perfusion with orthograde or retrograde flow in patients with irresectable liver metastases using percutaneous balloon catheter techniques: a phase I and II study.

BackgroundIsolated hepatic perfusion for irresectable metastases confined to the liver has reported response rates of 50% to 75%. Magnitude, costs, and nonrepeatability of the procedure are its major drawbacks. We developed a less invasive, less costly, and potentially repeatable balloon catheter–mediated isolated hypoxic hepatic perfusion (IHHP) technique.MethodsIn this phase I and II study, 18 consecutive patients with irresectable colorectal or ocular melanoma hepatic metastases were included. Two different perfusion methods were used, both with inflow via the hepatic artery, using melphalan 1 mg/kg. In the first eight patients, the portal vein was occluded, and outflow was via the hepatic veins into an intracaval double-balloon catheter. This orthograde IHHP had on average 56% leakage. In next 10 patients, we performed a retrograde outflow IHHP with a triple balloon blocking outflow into the caval vein and allowing outflow via the portal vein. The retrograde IHHP still had 35% leakage on average.ResultsAlthough local drug concentrations were high with retrograde IHHP, systemic toxicity was still moderate to severe. Partial responses were seen in 12% and stable disease in 81% of patients. The median time to local progression was 4.8 months.ConclusionsWe have abandoned occlusion balloon methodology for IHHP because it failed to obtain leakage control. We are presently conducting a study using a simplified surgical retrograde IHHP method, in which leakage is fully controlled, which translates into high response rates.

Detection of melanoma micrometastases in sentinel nodes – The cons

The sentinel node (SN) procedure in melanoma patients is important for prognostic information, but has no impact on survival. Micrometastases are identified in approximately 20% of the SNs. When a Completion Lymph Node Dissection (CLND) is performed for positive SN, additional non-SN lymph node involvement is also approximately 20%. Several classification criteria have been proposed to identify patients with SNs without a risk for additional nodes or a good prognosis. Micro anatomic analyses of metastatic SNs suggest that patients with sub-micrometastases (<0.1mm) in the SN may be judged as SN negative. Patients with this limited tumor burden in their SN have an excellent prognosis and are highly unlikely to benefit from CLND. New techniques such as ultrasound of the lymph nodal basin can be promising as an alternative for SN biopsy.

The role of isolated limb perfusion for melanoma confined to the extremities

Isolated limb perfusion with Melphalan is the best treatment option to control symptomatic multiple small in-transit metastases. When lesions are bulky, Isolated Limb Perfusion (ILP) with Tumor Necrosis Factor (TNF) + Melphalan is superior as in soft tissue sarcoma. TNF changes the pathophysiology, greatly enhances the uptake of Melphalan and destructs selectively the vasculature of large tumors. To date, ILP is not indicated in an adjuvant setting.

Giant solitary fibrous tumour of the liver

BackgroundSolitary fibrous tumour (SFT) is an uncommon mesenchymal neoplasm that most frequently affects the pleura, although it has been reported with increasing frequency in various other sites such as in the peritoneum, pericardium and in non-serosal sites such as lung parenchyma, upper respiratory tract, orbit, thyroid, parotid gland, or thymus. Liver parenchyma is rarely affected. Clinically, SFTs cause symptoms after having reached a certain size or when vital structures are involved. In recent years, SFTs are more often identified and distinguished from other tumours with a similar appearance due to the availability of characteristic immunohistochemical markers.Case presentationIn this manuscript we report the case of a large tumour of the liver, which was histologically diagnosed as a SFT, and showed involvement of a single hepatic segment. Because of the patients presentation and clinical course, it may represent a radiation-induced lesion.ConclusionWhen a SFT has been diagnosed, surgery is the treatment of choice. The small number of patients with a SFT of the liver and its unknown natural behaviour creates the need to a careful registration and follow-up of all identified cases

When to perform surgery in stage IV melanoma patients

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 E-mail Information@Karger.de www.karger.com nal, adrenal and splenic metastases are known examples in melanoma patients which can lead to signs of obstruction, bleeding and/or pain and good palliation has been described in these patients [4–6]. Also patients with metastases that may cause significant symptoms before the patient dies of the disease might be candidates for palliative surgery. This requires considerable judgement about whether the potential benefits of the proposed surgery outweigh the risks in the individual patient. In this situation the surgeon is trying to protect the quality of life with minimal morbidity and no mortality of the procedure. This difficult decision requires knowledge of the biology of the disease and clinical performance of the patient and is often made in multidisciplinary teams where medical oncologists and radiotherapists are also involved. Another reason to perform surgery in patients with stage IV melanoma is to aim for a potentially curative resection. This option is not often possible and results may reflect a more favourable biology of the disease, rather than just an independent therapeutic benefit of the surgical procedure. However, several studies have been presented demonstrating 5-year survival rates between 20 and 30% in selected patients with completely resected metastases [7, 8]. Unfortunately, most published data for metastasectomy are from single-institutional series and comparison between different reports is difficult. Morton et al. have reported the results of a multicentre randomised trial in stage IV patients who underwent complete surgical resection [9]. Patients in this trial were randomised to receive adjuvant onamelatucel-L (Canvaxin®) or placebo. Although the trial was stopped after an interim analysis because no effect was demonstrated of the studied drug, important observations could be made. First, selection of patients for surgery in stage IV melanoma is essential, because only patients with 3 or fewer visceral sites who could be treated with complete surgical resections could enter this trial. Second, treatment was uniformly performed in all participating In this issue of ONKOLOGIE, Tomov et al. [1] describe a young patient with stage IV melanoma treated with multiple surgical resections of metastatic disease leading to an apparent cure. In daily practice, the majority of stage IV melanoma patients present with multiple unresectable metastatic lesions and survival is generally poor, with 3-year overall survival rates of approximately 15% [2]. There is no systemic therapy for these patients that can be considered standard. In spite of response rates of up to 50% with some biochemotherapy regimens, superiority in terms of survival has never been demonstrated over single or polychemotherapeutic regimens, which by themselves have not been proven to be superior to treatment with dacarbazine (DITC) alone [3]. So the crucial question is how do we identify patients that may benefit from a surgical approach? Clearly the answer is by selecting out patients with the right biology. This biology may be characterised by the presence of oligometastatic disease and we should base our decisions on site(s) and number of the metastases, the presence or absence of certain biomarkers, and a history of slow versus rapid progression of the patients’ disease. The patient in this case report is one of numerous, highly selected patients reported in the literature who benefit from an aggressive surgical approach in metastasised melanoma patients. In general, the two major reasons to perform surgery in stage IV melanoma patients are palliation and cure. Palliation is considered for patients who have surgically accessible metastases that are symptomatic and negatively influencing the quality of life. The value of surgery for palliation is vastly underestimated. Unfortunately many opportunities to achieve local control are missed and systemic therapy or radiation therapy is given in situations where a relatively simple surgical procedure would have provided the simplest and quickest solution. Especially cutaneous, subcutaneous and distant lymph node metastases can cause local problems that can easily and most effectively be dealt with surgically. But also gastrointestiWhen to Perform Surgery in Stage IV Melanoma Patients?